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1
Du, Ying. "Ischemic and pharmacological preconditioning of rat myocardium : effects on ischemia-reperfusion injury /." View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BICH%202005%20DU.
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Ko, Robert K. M. "Molecular aspects of myocardial ischemia/reperfusion injury and the protective effects of allopurinol." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/30699.
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A growing body of evidence has now accumulated supporting the involvement of oxygen-derived free radicals in the development of myocardial ischemia/reperfusion (I/R) injury. We have, therefore, undertaken the present study to examine (1) I/R-related alterations in myocardial antioxidant capacity in pentobarbital anesthetized open-chest rabbits subjected to left circumflex coronary artery ligation followed by reperfusion; (2) the protective effects of pretreatrnent with allopurinol or the 21-aminosteroid U74006F; (3) alternative mechanisms to xanthine oxidase inhibition for allopurinol protection against I/R injury; and (4) the effect of allopurinol treatment on the antioxidant capacity of erythrocytes in pigs used in a heart-lung transplantation study.
In the rabbit myocardium, a marked impairment in myocardial antioxidant capacity developed in association with the onset of irreversible injury, as reflected in the enhancement in glutathione (GSH) depletion and formation of thiobarbituric acid-reactive substances (TBARS) following in vitro incubation of tissue homogenate with tert-butylhydroperoxide (TBHP). During the course of post-ischemic reperfusion, the protracted time-course of
alterations in antioxidant capacity dissociated them from the early burst of radical formation known to occur at the onset of post-ischemic reperfusion of the myocardium. When
the time-dependent changes in functional indices of antioxidant status (TBHP-induced GSH depletion and formation of TBARS) were analysed in relation to activities of antioxidant enzymes, evidence suggestive of functionally relevant impairments in Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and glutathione reductase (GRD) activities was found. These results and our demonstration of significant decreases in the activity of GSH-dependent antioxidant enzymes under acidotic conditions suggest that a transient impairment in the functioning of antioxidant enzymes may be involved in triggering irreversible myocardial I/R injury.
Repetitive brief episodes of I/R produced a
progressive decrease in myocardial ATP levels, which was not associated with any detectable changes in myocardial antioxidant capacity. Ischemic preconditioning produced by brief episodes of I/R did not affect the severity of subsequently induced I/R injury. These results suggest that brief episodes of myocardial ischemia do not produce oxidative tissue damage and the ischemia-induced depletion in myocardial ATP level is at least partially dissociable from the I/R-related impairment in tissue antioxidant capacity.
Isolated Langendorff-perfused rabbit hearts subjected to I/R did not show any changes in antioxidant capacity. However, when intact hearts were subjected to ischemia in vivo and a subsequent reperfusion in vitro, an impairment in myocardial antioxidant capacity became apparent. These
results suggest that blood elements, possibly activated neutrophils, may be a crucial factor involved in the development of I/R-induced oxidant injury.
Chronic allopurinol pretreatment (1 mg/ml in drinking water or approximately 75 mg/kg/day) for 7 days prior to ischemia provided significant protection against I/R-induced alterations in myocardial antioxidant capacity, but not the decrease in tissue ATP levels. This chronic allopurinol regimen was found to enhance myocardial GRD activity in nonischemic
tissue. In addition, both allopurinol and oxypurinol inhibited the transition metal ion-catalysed ascorbate oxidation and lipid peroxidation in vitro, likely as a consequence of their metal chelating properties. Similarly, myoglobin-TBHP-catalysed oxidation of uric acid and lipid peroxidation were also suppressed by allopurinol. All these suggest that allopurinol may favorably alter myocardial antioxidant capacity directly by virtue of its transition metal chelating properties and its antioxidant actions in myoglobin-mediated oxidative processes.
The acute administration of 21-aminosteroid U74006F (3 mg/kg, i.v) under conditions comparable to those known to protect against trauma-induced damage in the central nervous system failed to reduce manifestations of oxidative injury in rabbit hearts subjected to ischemia and reperfusion. Although reactive oxy-radicals have been implicated in both types of tissue damage, the observed difference in susceptibility to protection by this steroidal antioxidant
suggests that the molecular mechanisms involved are not identical.
In the heart-lung transplantation study, erythrocytes from allopurinol-treated pigs (given repeatedly at an oral dose of 50 mg/kg) showed a time/dose-dependent increase in antioxidant capacity as reflected in the decrease in malondialdehyde production following in vitro oxidative challenge. The extent of red cell protection in both donor and recipient animals correlated significantly with the functional viability of the transplanted lung tissue, as assessed by tissue water content. These results suggest that the measurement of erythrocyte antioxidant capacity may provide an useful assessment of generalized alterations in tissue antioxidant status produced by pharmacological interventions.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
3
Löwbeer, Christian. "Cardiac troponin T in clinical and experimental studies /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-426-6/.
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Bhimji, Shabir. "Myocardial ischemic injury in experimental diabetes." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25562.
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The nature and extent of myocardial ischemic injury (Mil) produced either by coronary artery ligation/reperfusion or by injection of isoproterenol
(ISO) was studied in the 10-week alloxan-diabetic rabbit. Prior to the induction of ischemic injury, investigation of the left ventricles of the diabetic rabbit after 10-weeks revealed significant magnesium depletion and inhibition of myofibrillar and sarcoplasmic reticulum ATPase activities. In addition, the activity of the lysosomal enzyme, N-acetyl-β-glucosaminidase was significantly increased in diabetic left ventricular homogenates. Ultrastructural studies revealed significant lipid and glycogen accumulation, dilatation of the sarcoplasmic reticulum and damage to the mitochondria in left ventricles of the diabetic animals.
Administration of ISO to both control and diabetic animals resulted
in atrial tachycardias and ventricular fibrillation. The severity of the arrhythmias and the overall mortality was the same in both groups of animals. Serum analyses revealed significantly greater increases in blood glucose, free fatty acids, total cholesterol and creatine kinase activity in the ISO-treated diabetic animals relative to ISO-treated controls. ISO treatment of both control and diabetic animals produced similar increases in heart weight, left ventricular weight and myocardial water content. Analyses of various subcellular organelle marker enzyme activities indicated a significantly greater decrease in the K⁺ ,Ca²⁺ -stimulated sarcoplasmic reticulum ATPase of ISO-treated diabetic animal hearts. In addition, significantly greater increases in Ca and hydroxyproline and decreases in the levels of ATP were evident in the ISO-treated diabetic animal hearts. Ultra-structural studies revealed significant damage to the mitochondria in both ISO-treated control and diabetic hearts, the magnitude of the damage being greater in the diabetic animals. Mitochondria from both groups of animals showed swelling and fragmentation, myofibrils appeared
as a homogeneous mass and did not show the characteristic Z-lines. Glycogen depletion and lipid accumulation was observed in both groups of animals. In addition, both groups of animals showed amorphous dense bodies in the mitochondria after ISO-treatment. After 40-minutes occlusion of the left circumflex coronary artery followed by 60-minutes of reperfusion, hemodynamic measurements revealed significant decreases in the left ventricular and systemic arterial pressures in the diabetic animals relative to controls. Analyses
of subcellular organelle enzymes from the ischemic tissue revealed that sarcolemmal Na⁺ ,K⁺ -ATPase, mitochondrial ATPase and sarcoplasmic reticulum ATPase activities were decreased after coronary occlusion in both control and diabetic animals. However, upon reperfusion, unlike the control, no recovery of the mitochondrial ATPase was observed in the diabetic animals. In addition, a further depression of both the sarcolemmal and sarcoplasmic reticulum ATPase activities were seen in the diabetic animals compared to controls on reperfusion. Ion measurements revealed a significant accumulation of calcium in both control and diabetic animals, the magnitude of the increase being greater in the diabetic animals. Similarly, both tissue ATP levels and the ability of the mitochondria to generate ATP were depressed in the diabetic animals as compared to controls following coronary artery occlusion and reperfusion. Following coronary artery ligation and reperfusion, the diabetic animals showed a significantly higher incidence of ventricular fibrillation and cardiogenic shock as compared to controls. Ultrastructural studies revealed myocardial
damage to both control and diabetic hearts following coronary artery ligation and reperfusion. However, the diabetic myocardium showed a higher incidence and frequency of hypercontraction bands, an increase in the amorphous dense bodies and slightly greater damage to the mitochondria.
Coronary artery ligation in conscious control, 6 and 12 week-diabetic rats resulted in post-ligation arrhythmias (especially ventricular fibrillation), the incidence of which was much greater in the diabetic animals. The mortality rate of 12-week diabetic rats undergoing coronary ligation was 100% within 1-7 minutes following ligation. No differences in occluded or infarcted zones of the surviving 6-week diabetic and control rats were detected. Analyses of ionic composition revealed a significant magnesium deficiency in the diabetic
hearts as compared to controls.
These data indicate that the diabetic animals show a greater susceptibility
of the myocardium to ischemic injury. Although numerous metabolic and chemical alterations are present in the diabetic myocardium,
it is possible that magnesium deficiency may be a factor determining
the higher incidence of arrhythmias and ischemic injury in diabetic animals.Pharmaceutical Sciences, Faculty of
Graduate
5
Nagra, Aarondeep Singh. "Investigation into the cardiotoxic effects of β-adrenergic receptor agonists in myocardial ischaemia/reperfusion injury." Thesis, Coventry University, 2016. http://curve.coventry.ac.uk/open/items/5dbd924b-a29f-4281-9f7c-bc14351cc294/1.
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The treatment of asthma still relies on primary therapy with bronchodilators; in particular β adrenergic receptor (bAR) agonists with a diverse range of short acting and long acting βARs available. An increase in the number of cardiovascular events with the use of bronchodilators have recently been reported including hypertrophy, heart failure, myocardial ischaemia and infarction. Several subtypes of βAR receptors exist including the β1 Adrenergic Receptor (β1AR) and β2 Adrenergic Receptor (β2AR), both located in the heart. The effects of selective β2AR agonists were investigated in the Langendorff model of myocardial ischaemia reperfusion injury, isolated perfused rat hearts underwent 35 minutes of ischaemia and 120 minutes of reperfusion. The selective β2AR long acting β agonists Formoterol and Salmeterol had no significant effect on infarct to risk ratio or time taken to depolarisation and hypercontracture in isolated cardiomyocytes. The non-selective β1AR agonist Isoproterenol has been show to induce myocardial ischaemia and infarction in rat hearts previously, here we demonstrated Isoproterenol (0.5μM) significantly decreased time taken to depolarisation and hypercontracture in isolated cardiomyocytes. The short acting β2AR agonist Salbutamol (0.01μ-1μM) significantly increased infarct to risk ratio in the Langendorff in addition to significantly decreasing time to hypercontracture in cardiomyocytes in the oxidative stress model highlighting a potential role of the mitochondrial permeability transition pore (mPTP). Activation of phosphorylated Akt and phosphorylated Erk1/2 via the PI3K/Akt signalling pathway and p44/p42 MAPK pathway were investigated by western blot analysis. Salbutamol significantly elevated expression of p-Akt in rat hearts exposed to reperfusion for 20 and 120 minutes whilst reducing expression of p-Erk. Recorded elevated cleaved caspase 3 expression in Salbutamol treated hearts can be associated as a marker of increased in cardiomyocyte cell death. The β1AR antagonist CGP 20712 was administered in the presence of Salbutamol with minimal reduction in infarct size in rat hearts recorded and no significant change in time taken to hypercontracture in isolated cardiomyocytes suggesting that Salbutamol mediated toxicity is via β2AR activation. Confirmation of this was verified with the β2AR antagonist ICI 118, 551. Significant decrease in infarct size was recorded in addition to a significant increase in time to hypercontracture in the oxidative stress model. Further to this, caspase 3 expression was significantly reduced in addition with p-Akt expression. With a potential role of the mitochondria and the mPTP contributing to Salbutamol induced myocardial injury, the Cyclophilin D inhibitor Cyclosporin A was administered in hearts and cardiomyocytes in the presence of Salbutamol. Infarct size was significantly reduced whilst time taken to hypercontracture significantly increased, suggesting that CsA treatment inhibits Salbutamol mediated injury via Cyclophilin D inhibition of the mPTP. To conclude, our results demonstrated that Salbutamol caused cardiotoxicity at tissue, cellular and protein level in conditions of ischaemia reperfusion injury. Further to this, inhibition of Cyclophilin D by CsA, or the use of the β2AR antagonist ICI 118, 551 inhibits Salbutamol induced toxicity.
6
Al-Rajaibi, Hajar M. "The role of caspase inhibitors in protecting the myocardium from ischemia reperfusion injury." Thesis, Coventry University, 2008. http://curve.coventry.ac.uk/open/items/7c1324d7-8e28-3a1c-009c-fc7aa0d874f8/1.
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Rapid restoration of blood flow to ischemic myocardium is essential, however it causes further injury called reperfusion injury. Apoptosis contributes significantly to cardiomyocyte cell death during ischemia reperfusion injury, in which caspase family proteases play an essential role as they are the executioners of apoptosis. Caspase inhibitors showed promising cardioprotective results when administered before ischemia or at the start of reperfusion. However, before applying them in pre clinical studies of myocardial ischemia, several investigations needed to be taken to determine their therapeutic window post reperfusion, their effect on functional recovery of myocardium post ischemia, their mechanism of action. Methods Isolated perfused rat hearts were subjected to 35 min ischemia followed by 2 hr reperfusion where caspase inhibitors [broad spectrum caspase inhibitor (ZVAD, 0.1µM), specific caspase 3 inhibitor (DEVD, 0.07µM)] were added at the start of reperfusion, 15, 30 and 60 min after starting reperfusion at the presence or absence of Wortmannin (WORT, 100nM, PI3-kinase inhibitor). Hearts underwent triphenyl tetrazolium staining for infarct size assessment, or were frozen for Western blot analysis. Freshly isolated adult rat ventricular myocytes were subjected to 6 hr hypoxia followed by either 18 hr, where caspase inhibitors (ZVAD, 25µM and DEVD, 25µM) were added at the start of reoxygenation, 15, 30 and 60 min after starting reoxygenation at the presence or absence of Wortmannin (WORT, 100nM). Cardiomyocytes were analysed for viability, apoptosis, necrosis and intracellular caspase-3 activity using flow cytometry analysis. Isolated adult rat ventricular papillary muscles were subjected to 35 min hypoxia followed by 100 min reperfusion where caspase inhibitors [ZVAD (0.1 µM, 2.5µM) and DEVD (2.5µM)] were added at the start of reperfusion throughout. Power output was measured using work loop technique.
7
Siu, Ada Hoi Ling. "Cardioprotective effects of herba cistanche on ischemia/reperfusion injury ex vivo and oxidative injury in vitro /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BICH%202008%20SIU.
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Whittaker, Ross J. "New roles for alpha B-crystallin in protecting the myocardium from ischemia/reperfusion injury." Diss., [La Jolla] : [San Diego] ; University of California, San Diego ; San Diego State University, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3336476.
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Tang, Wai-ho Jack, and 鄧偉豪. "Role of polyol pathway in ischemic and hyperglycemic cardiomyopathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45197404.
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10
Hasanally, Devin. "Bioactive oxidized phosphatidylcholines cause apoptotic cell death in cardiomyocytes during ischemia reperfusion." Springer-Verlag New York, 2014. http://hdl.handle.net/1993/30363.
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The main treatment for myocardial infarction is early reperfusion of ischemic tissue. Ischemia and reperfusion (IR) produces reactive oxygen species that oxidize membrane phospholipids. The production of oxidized lipids and their role on cell death in cardiac IR injury is unknown. Using in vitro model of IR, our goal was to identify oxidized phosphatidylcholines (OxPC) from cardiomyocytes, to determine their bioactivity on cardiomyocyte viability and mitochondrial permeability, and using an OxPC specific EO6 antibody inhibit OxPC activity on cardiomyocytes.
Rat cardiomyocytes were exposed to IR and lipid extracts underwent lipidomic analysis with HPLC-MS/MS to quantitate 82 novel OxPC species. Cell viability and mitochondrial permeability were determined in vehicle control, non-oxidized control PC, and fragmented OxPC molecules. EO6 antibody was applied and cell viability was assessed.
Cardiomyocytes under IR demonstrated increased relevant OxPCs particularly fragmented species. OxPC treatment resulted in loss of cardiomyocyte viability, increased mitochondrial permeability when compared to control. EO6 antibody blocked the loss of cardiomyocyte viability.
We have shown for the first time that OxPCs are generated cardiomyocytes during IR and they have detrimental effects on cardiomyocyte viability. Additionally the EO6 antibody inhibits the bioactivity of the OxPCs on cardiomyocytes and could be part of a future treatment regimen.
11
Gasser, Robert N. A. "Microelectrode study of the mechanisms of ionic and electrical changes during simulated ischaemia in isolated cardiac muscle." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670316.
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Morrison, Lisa E. "A cardioprotective role for the small heat shock protein, alpha B-crystallin, in ischemia-reperfusion injury /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112973.
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Rasmussen, Tyler Paul. "Mitochondrial calcium uniporter is a nodal regulator of physiological and pathological stress responses in myocardium." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3169.
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A long held hypothesis in mitochondrial biology holds that increases in mitochondrial Ca2+ levels stimulate the activity of matrix dehydrogenases that catalyze production of NADH and eventually donate electrons to electron transport in order to increase ATP formation. At the same time, mitochondrial Ca2+ overload is a deleterious event leading to opening of the mitochondrial permeability transition pore, increasing reactive oxygen species and initiating pathways that contribute to cell death. These fundamental hypotheses are best studied in the heart because of the critical energy supply-demand relationship in myocardium, but were untestable in vivo until the discovery of the mitochondrial Ca2+ uniporter (MCU). The molecular identity of the MCU pore forming subunit was recently discovered, which allowed me to study a transgenic mouse with myocardial delimited expression of a dominant negative MCU.
My lab developed mice with myocardial-delimited transgenic expression of a dominant negative MCU to test these fundamental hypotheses and to determine how MCU controls physiological and pathological stress responses in vivo, ex vivo, and in situ. My studies provide new, unanticipated information that contributes to our understanding the relationship between mitochondrial Ca2+, oxygen utilization, cardiac pacemaking and pathologic stress responses in heart. Here, I show that mice with myocardial-targeted MCU inhibition have hearts with surprisingly high oxygen consumption rates due to elevated cytoplasmic Ca2+ in response to physiological stress. Loss of MCU effectively preserved inner mitochondrial membrane potential and prevented an oxidative burst thought to drive myocardial injury and death, but nevertheless failed to protect myocardium from ischemia-reperfusion injury. Increases in oxygen consumption, elevation in cytoplasmic Ca2+ and transcriptional reprogramming mitigate the protective actions of MCU inhibition in vivo. Mice with myocardial selective MCU inhibition have a reduced response to isoproterenol-induced heart rate increase but have normal baseline heart rates. My studies provide novel insight into how MCU contributes to myocardial Ca2+ homeostasis, metabolism, and transcription leading to surprising actions on physiological and pathophysiological responses in heart.
14
Aune, Sverre Erik. "The Role of Reactive Oxygen Species in Post-Ischemic Low Flow in the Myocardium." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338233129.
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Martindale, Joshua J. "Protecting the myocardium from ischemia and reperfusion injury via inducible activation of ATF6 or constitutive expression of MKK6 /." Diss., Connect to a 24 p. preview or request complete full text in PDF formate. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3236641.
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Louw, Rehette. "The signaling pathways involved in the cardioprotection offered by insulin to the global low flow ischaemic/reperfused myocardium." Thesis, Stellenbosch : Stellenbosch University, 2001. http://hdl.handle.net/10019.1/52577.
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Thesis (MSc)--Stellenbosch University, 2001.ENGLISH ABSTRACT: Introduction: It is well documented that insulin offers cardioprotection under ischaemic stress. In the past it was believed that the protective effects of insulin, such as the (a) recruitment of glucose transporters to enhance glucose entry into the cell, (b) stimulation of glycolysis, (c) enhancement of glycogen synthesis, (d) improved protein synthesis, and (e) positive inotropic and chronotropic properties, were metabolic of origin, but lately the emphasis has shifted towards the diverse signal transduction pathways elicited by insulin. Although these beneficial effects of insulin on ischaemia/reperfusion induced injury have been studied for many years, the exact protective mechanism is still not resolved. Aim: To investigate the influence of insulin on the signaling pathways as a possible protective mechanism against ischaemia/reperfusion and therefore to investigate the possible roles and cross signaling of cyclic adenosine monophosphate (cAMP), protein kinase B (PKB) and p38 mitogen activated protein kinase (p38 MAPK) in the cardioprotection offered by insulin to the reperfused, ischaemic myocardium. Materials and methods: Isolated rat hearts were perfused retrogradely in accordance with the Langendorff technique (95%02, 5% C02). After 30 min of stabilization, hearts were subjected to 30 min global low flow ischaemia (0,2 ml/min), followed by 30 min of reperfusion. Hearts perfused with standard Krebs Henseleit solution containing 5 mM glucose were compared to hearts perfused with a perfusion solution containing 5 mM glucose and 0,3 IlIU/ml insulin. Wortmannin was added during either ischaemia or reperfusion. Left ventricular developed pressure (LVDP), rate pressure product (RPP), tissue cAMP and PKB and p38 MAPK activation were measured. Results: Insulin treated hearts showed improved functional recovery (P<0.05) during reperfusion after ischaemia vs. non-insulin treated hearts (85.5±4.6% vs. 44.8±4.9%). However, the addition of wortmannin (a Pl3-kinase inhibitor) to the perfusion solution during either ischaemia or reperfusion abolished the improved recovery. At the end of ischaemia, cAMP levels of the insulin treated hearts were elevated significantly, while the cAMP content in the non-insulin treated hearts returned to control levels. Addition of wortmannin during ischaemia abolished this rise in cAMP. Wortmannin added during reperfusion only did not alter the levels of cAMP at the end of reperfusion. Activation of p38 MAPK was transient during ischaemia for both insulin and non-insulin treated hearts. Addition of wortmannin during ischaemia did not alter p38 MAPK levels at the end of ischaemia. P38 MAPK was activated significantly (P<0.001) in the non-insulin treated hearts vs. insulin treated hearts during reperfusion. Wortmannin, added at the onset of reperfusion, could partially abolish the effects of insulin to suppress p38 MAPK activation after 30 min of reperfusion. Activation of PKB in insulin treated hearts was significantly higher than non-insulin treated hearts during stabilization and early ischaemia. This activity was depressed by 30 min of ischaemia in both presence and absence of insulin. Wortmannin, when added before induction of ischaemia did not further lower this. The presence of insulin resulted in occurrence of strong PKB activation during reperfusion, peaking at 15 minutes and diminishing at 30 minutes. Wortmannin, added at the onset of reperfusion, abolished PKB activity measured at the end of reperfusion. Conclusion: Insulin exerted a positive inotropic effect and delayed the onset to ischaemic contracture. Inhibition of Pl3-kinase by wortmannin abolished the protective effects of insulin, arguing for an insulin stimulated PKB involvement in cardiac protection. Insulin also increased cAMP production and attenuated activation of p38 MAPK, both associated with improved recovery. This evidence suggested possible cross signaling between different signaling pathways.
AFRIKAANSE OPSOMMING: Agtergrond: Insulin beskerm harte wat aan isgemiese stres blootgestel word. Alhoewel hierdie voordelige effekte van insulien reeds vir verskeie jare bestudeer is, is die presiese meganisme waarmee insulien die hart beskerm steeds nie duidelik nie. Navorsers het die beskermende effekte van insulien aan metaboliese gevolge soos: (a) verhoogde glukose transport d.m.v. inspanning van meer glukose transporters (b), stimulering van glikolise, (c) vebeterde glikogeensintese, (d) verhoogde proteiensintese, en (e) die positiewe inotropiese en chronotropiese eienskappe van insulien toegeskryf. Onlangs het die fokus verskuif na ander diverse seintransduksiepaaie. Doel: Die doel van hierdie studie was dus om die moontlike betrokkenheid van hierdie sientransduksiepaaie asook die interaksie tussen sikliese adenomonofosfaat (cAMP), proteïn kinase B (PKB) en p38 MAPK in die beskerming wat insulien aan die isgemiese, gereperfuseerde miokardium bied, te bestudeer. Materiale en Metodes: Geïsoleerde rotharte is geperfuseer in ooreenstemming met die Langendorff metode. Na 30 min van stabilisasie is harte blootgestel aan 30 min. globale lae vloei isgemie (0,2 ml/min), en daarna is harte vir 30 min. geherperfuseer. Harte wat geperfuseer is met 'n perfusaat wat 5mM glukose bevat is vergelyk met harte wat geperfuseer is met 'n perfusaat wat 5mM glukose en 0,3 ~IU/ml insulien bevat. Sommige harte is geperfuseer met 'n perfusie oplossing waar wortmannin bygevoeg is tydens óf isgemie óf tydens herperfusie. Linker ventrikulêre ontwikkelde druk (LVDP), tempo-druk produk (RPP), weefsel cAMP-vlakke asook PKB en p38 MAPK aktiwiteit is gemeet. Resultate: Insulien-behandelde harte het funksioneel beduidend beter herstel tydens herperfusie na isgemie as harte wat nie met insulien behandel is nie (85.5±4.6% vs. 44.8±4.9%). Byvoeging van wortmannin by die perfusie oplossing tydens óf isgemie óf reperfusie, het die toename in herstel wat gesien is in die insulien-behandelde harte, opgehef. Die cAMP vlakke in die insulienbehandelde harte het aan die einde van isgemie beduidend gestyg (P<0.001), terwyl vlakke in harte wat nie met insulien behandel is nie, na kontrole vlakke teruggekeer het. Die teenwoordigheid van wortmannin in die perfusie oplossing tydens isgemie, het die styging in cAMP voorkom , terwyl die byvoeging van wortmannin tydens herperfusie. nie die cAMP vlakke beïnvloed het nie. Die aktivering van p38 MAPK tydens isgemie was van verbygaande aard in beide die insulien-behandelde harte en harte wat nie met insulien behandel is nie. Die byvoeging van wortmannin tydens isgemie het nie die p38 MAPK aktivering beïnvloed nie. P38 MAPK is beduidend geaktiveer tydens herperfusie in harte wat nie met insulien behandel is nie vergeleke met die insulien-behandelde harte. Die byvoeging van wortmannin tydens reperfusie kon die effek van insulien om p38 MAPK aktivering te onderdruk, gedeeltelik ophef. PKB aktivering tydens die stabilisasie fase en vroeë isgemie was beduidend hoër in die insulien-behandelde harte vs. die harte wat nie met isulien behandel is nie. Die aktiwiteit is onderdruk deur 30 min isgemie ongeag die teenwoordigheid van insulien. Die byvoeging van wortmannin tydens isgemie het PKB aktivering nie verder verlaag nie. Die teenwoordigheid van insulien het 'n sterk aktivering van PKB tydens herperfusie veroorsaak met 'n piek na 15 min en 'n verlaging na 30 min. Wortmannin bygevoeg aan die begin van herperfusie, het PKB aktiwiteit opgehef aan die einde van reperfusie. Opsomming: Insulien het 'n positiewe inotropiese invloed gehad, en het die begin van isgemiese kontraksie vertraag. Die inhibisie van Pl3-kinase deur wortmannin het die beskermende effekte van insulin opgehef, wat 'n insulin gestimuleerde PKB betrokkenheid aandui. Insulien het ook verhoogte cAMP produksie en verlaagde p38 MAPK aktivering tot gevolg gehad, en beide is geassosieer met verbeterde herstel. Hierdie resultate dui dus op moontlike interaksie tussen die verskillende seintransduksiepaaie.
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Fan, Wen Jun. "The role of protein phosphatases in myocardial ischaemia and reperfusion." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21615.
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Thesis (MScMed)--Stellenbosch University, 2008.ENGLISH ABSTRACT: Protein kinases and phosphatases play important roles in the phosphorylation state of intracellular proteins under both physiologic and pathophysiologic conditions. Compared to the large number of studies investigating the significance of kinases, in particular the mitogen-activated protein kinases (MAPKs) in myocardial ischaemia/reperfusion and ischaemic preconditioning, relatively few studies have been done on the protein phosphatases in this scenario. Although several role players in the signal transduction cascade of ischaemia/reperfusion and ischaemic preconditioning have been identified thus far, the exact mechanism of cardioprotection still remains unclear. Previous studies from our laboratory have shown that the stress kinase, p38 MAPK, has a dual role in preconditioning: it acts as trigger of the process, while attenuation of its activation during sustained ischaemia and reperfusion is required for cardioprotection. Since the activation of p38 MAPK is dependent on both the upstream kinases for phosphorylation and phosphatases for dephosphorylation, we hypothesized that the balance between the activation state of the MAPKs and the induction of phosphatases may play a major role in determining the fate of cardiomyocytes exposed to ischaemic stress. The objectives of this study were: (i) to assess the activity of the myocardial protein phosphatases (PSPs and PP1) during sustained ischaemia and during reperfusion of non-preconditioned and ischaemic preconditioned hearts; (ii) to evaluate the significance of these phosphatases in ischaemia/reperfusion as well as in ischaemic preconditioning using available appropriate inhibitors; (iii) to give particular attention to the role of the phosphatase, mitogen-activated protein kinase phosphatase-1 (MKP-1), in ischaemia/reperfusion. MKP-1 is upregulated by stress conditions and selectively inactivates p38 MAPK by dephosphorylation of the regulatory Thr and Tyr residues. The glucocorticoid, dexamethasone which increases MKP-1 expression, was used as agonist to upregulate MKP-1 experimentally. The isolated perfused working rat heart was used as experimental model. After stabilization, hearts were subjected to either a one-cycle or multi-cycle ischaemic preconditioning protocol, followed by sustained global or regional ischaemia and reperfusion. Non-preconditioned hearts were subjected to ischaemia/reperfusion only. For Western blot analysis of MAPKs, PKB/Akt and MKP-1, hearts were freeze-clamped at different times during the perfusion protocol. Endpoints were infarct size, functional recovery and phosphorylation of the MAPKs (ERK and p38 MAPK) and PKB/Akt during reperfusion. Expression of MKP-1 was monitored. The results obtained showed that activation of PSPs and PP1 does not occur during sustained global ischaemia or reperfusion of non-preconditioned and preconditioned hearts. The role of the phosphatases was subsequently further investigated using two inhibitors namely cantharidin (5 μM, a concentration which inhibits both PP1 and PP2A) and okadaic acid (7.5 nM, a concentration which inhibits PP2A selectively). Administration of cantharidin or okadaic acid during the preconditioning phase, completely abolished preconditioning induced cardioprotection as indicated by mechanical failure during reperfusion and increased infarct size, associated with increased phosphorylation of p38 MAPK and PKB/Akt and dephosphorylation of ERK42/44. These results suggest a role for PP2A in the trigger phase of preconditioning. Administration of cantharidin or okadaic acid during early reperfusion of preconditioned hearts improved functional recovery. This was associated with increased phosphorylation of ERK42/44 and PKB, but not p38 MAPK. Dexamethasone, administered intraperitoneally to rats for 10 days (3mg/kg/day) or directly added to the perfusate (1 μM) resulted in significant cardioprotection of hearts subjected to 20 min sustained global ischaemia, followed by 30 min reperfusion. This is associated with a marked upregulation of MKP-1 and dephosphorylation of p38 MAPK during reperfusion. These studies suggest that the phosphatases are definitely involved in the phenomenon of ischaemia/reperfusion and ischaemic preconditioning. However, it also become clear that extensive further research is required to fully elucidate which phosphatases are involved and the mechanisms thereof. Due to the large size of the protein phosphatase family, this may prove to be a formidable task and far beyond the scope of this thesis. The results also suggested that pharmacological targetting of phosphatases involved in phosphorylation of the reperfusion injury salvage kinase (RISK) pathway (e.g. ERK42/44 and PKB/Akt) or dephosphorylation of pro-apoptotic kinases, such as p38 MAPK, may have significant clinical potential.
AFRIKAANSE OPSOMMING: Proteïenkinases en fosfatases speel 'n belangrike rol in die fosforileringstatus van intrasellulêre proteïene in beide fisiologiese en patofisiologiese toestande. In teenstelling met die groot aantal studies gedoen ten einde die rol van die kinases, veral die mitogeen-geaktiveerde proteïenkinases (MAPKs), in iskemie/herperfusie en iskemiese prekondisionering te ondersoek, is relatief min bekend aangaande die rol van die fosfatases in hierdie scenario. Hoewel verskeie rolspelers in die seintransduksieprosesse van iskemie/herperfusie en iskemiese prekondisionering reeds geïdentifiseer is, is die presiese meganisme van miokardiale beskerming steeds onbekend. Vroeëre studies vanuit ons laboratorium het getoon dat die streskinase, p38 MAPK, 'n tweeledige rol in prekondisionering speel: dit is 'n sneller ("trigger") van die proses, terwyl verlaagde aktivering tydens volgehoue iskemie en herperfusie, noodsaaklik vir beskerming is. Ons hipotese is dus dat die balans tussen die aktiveringstatus van die MAPKs en induksie van fosfatases die oorlewing van kardiomiosiete blootgestel aan iskemiese stres, bepaal. Die doelwitte van hierdie studie was: (1) bepaling van die aktiwiteit van miokardiale proteïen fosfatases (PSPs en PP1) tydens volgehoue iskemie en herperfusie van nie-geprekondisioneerde en iskemies-geprekondisioneerde harte; (ii) evaluering van die belang van fosfatases in iskemie/herperfusie beskadiging sowel as in iskemiese prekondisionering deur van geskikte inhibitore gebruik te maak; (iii) ondersoek na die rol van die fosfatase, mitogeen-geaktiveerde proteïen kinase fosfatase-1 (MPK-1) in iskemie/herperfusie beskadiging. Dit is bekend dat MKP-1 deur strestoestande opgereguleer word en p38 MAPK selektief deur defosforilasie van die regulatoriese Thr en Tyr residue inaktiveer word. Die glukokortikoïed, deksametasoon, wat MKP-1 uitdrukking stimuleer, is as agonis gebruik ten einde MKP-1 eksperimenteel op te reguleer. Die geïsoleerde, geperfuseerde werkende rothart is as eksperimentele model gebruik. Na stabilisasie, is die harte aan 'n enkel- of veelvuldige siklus iskemiese prekondisioneringsprotokol onderwerp, gevolg deur volgehoue globale of streeksiskemie. Nie-geprekondisioneerde harte is slegs aan iskemie/herperfusie onderwerp. Harte is op verskillende tye tydens die perfusieprotokol gevriesklamp vir Western blot analise van die MAPKs, PKB/Akt en MKP-1. Infarktgrootte en funksionele herstel tydens herperfusie is as indikators van iskemiese beskadiging gebruik. Fosforilasie van MAPKs en PKB/Akt sowel as uitdrukking van MKP-1 tydens vroeë herperfusie is gemonitor. Die resultate toon dat aktivering van PSP en PP1 tydens volgehoue iskemie en herperfusie nie plaasvind nie. Die rol van die fosfatases is verder ondersoek deur van twee inhibitore gebruik te maak, naamlik cantharidin (5 μM inhibeer beide PP1 en PP2A) en okadaic suur (7.5 nM inhibeer PP2A selektief). Toediening van of cantharidin of okadaic suur tydens die prekondisioneringsprotokol, hef prekondisionering-geïnduseerde beskerming totaal op, soos aangetoon deur hartversaking tydens herperfusie en 'n toename in infarktgrootte, tesame met 'n toename in die fosforilering van p38 MAPK en PKB/Akt en defosforilering van ERK42/44. Hierdie waarnemings dui op 'n rol vir PP2A as sneller in prekondisionering. Toediening van hierdie inhibitore tydens vroeë herperfusie het ook die miokardium beskerm, soos aangetoon deur 'n verbeterde meganiese herstel van geprekondisioneerde harte, tesame met ‘n verhoogde fosforilering van ERK42/44 en PKB (maar nie p38 MAPK nie). Deksametasoon, intraperitoneaal toegedien, vir 10 dae (3mg/kg/dag) of direk by die perfusaat gevoeg (1μM), het tot 'n hoogs beduidende beskerming teen iskemiese beskadiging gelei van harte blootgestel aan 20 min globale iskemie en 30 min herperfusie. Hierdie toename in funksionele herstel en afname in infarktgrootte het met 'n toename in MKP-1 uitdrukking en defosforilasie van p38 MAPK gepaard gegaan. Bogenoemde resultate dui op 'n definitiewe betrokkenheid van fosfatases in iskemie/herperfusie en iskemiese prekondisionering. Dit is egter ook duidelik dat intensiewe verdere navorsing benodig word om die presiese rol van die fosfatases te bepaal. Vanweë die grootte van die fosfatase familie, val dit egter buite die beskek van hierdie studie. Ten slotte, die resultate toon dat farmakologiese manipulasie van fosfatases betrokke by die fosforileringstatus van anti-apoptotiese kinases soos ERK42/44 en PKB/Akt en defosforilasie van pro-apoptotiese kinases, soos p38 MAPK, besondere kliniese toepassings mag hê.
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Messina, Julia Antoinette. "Molecular Localization of Hypoxia Inducible Factor-1-Alpha in Post-Ischemic Myocardium Following in Vivo Prolyl-4 Hydroxylase-2 Gene Silencing." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/2197.
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Wang, Xiaohui. "Role of TLRs, Hippo-YAP1 Signaling, and microRNAs in Cardiac Repair and Regeneration of Damaged myocardium During Ischemic Injury." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3287.
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Cardiovascular disease is a leading cause of death in the United States. Toll-like receptor (TLR)-mediated pathways have been demonstrated to play a role in myocardial ischemia/reperfusion (I/R) injury. We and others have shown that PI3K/Akt signaling is involved in regulating cellular survival and protecting the myocardium from I/R induced injury. In this dissertation, we provide compelling evidence that miR-125b serves to “fine tune” TLR mediated NF-kB responses by repressing TNF-a and TRAF6 expression. We constructed lentiviral expressing miR-125b, delivered it into the myocardium. The data showed that delivery of lentivirus expressing miR-125b significantly reduces myocardial infarct size and improves cardiac function in I/R hearts. Mechanistic studies demonstrated that miR-125b negatively regulates TLR mediated NF-kB activation pathway by repressing TNF-a and TRAF6 expression in the myocardium.
We also observed that transfection of the myocardium with lentivirus expressing miR-214 markedly attenuates I/R induced myocardial infarct size and cardiac dysfunction. We demonstrated that miR-214 activates PI3K/Akt signaling by targeting PTEN expression in the myocardium.
We also investigated the role of TLR3 in neonatal heart repair and regeneration following myocardial infarction (MI). Wild type (WT) neonatal mice showed fully cardiac functional recovery and small infarct size, while TLR3 deficient mice exhibited impaired cardiac functional recovery and large infarct area after MI. Poly (I:C), a TLR3 ligand, administration significantly enhances glycolysis, YAP1 activation and the proliferation of WT neonatal cardiomyocytes. 2-deoxyglucose (2-DG), a glycolysis inhibitor treatment abolished cardiac functional recovery and YAP1 activation in neonatal mice after MI. In vitro either inhibition of glycolysis by 2-DG or inhibition of YAP1 activation prevents Poly (I:C) induced YAP1 activation and neonatal cardiomyocyte proliferation. Importantly, YAP1 activation increases miR-152 expression, leading to cardiomyocyte proliferation through suppression P27kip1 and DNMT1 expression.
We conclude that microRNAs play an important role in TLR modulation induced protection against myocardial I/R injury by increasing the activation of PI3K/Akt signaling pathway, decreasing TLR/NF-kB mediated inflammatory response, and suppressing activation of apoptotic signaling following myocardial I/R injury.
In addition, TLR3 is an essential for neonatal heart repair and regeneration after myocardial infarction. TLR3 modulation could be a novel strategy for heart regeneration and repair.
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Kvitting, John-Peder Escobar. "Quantification of cardiovascular flow and motion : aspects of regional myocardial function and flow patterns in the aortic root and the aorta /." Linköping : Univ, 2004. http://www.bibl.liu.se/liupubl/disp/disp2004/med832s.pdf.
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Pucheu, Sylvie. "Contribution à l'étude des manifestations physiopathologiques liées au stress oxydatif intervenant lors de la reperfusion du myocarde ischémique : rôle des oligoéléments et essais de protection par des molécules antioxydantes." Université Joseph Fourier (Grenoble ; 1971-2015), 1994. http://www.theses.fr/1994GRE10180.
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Le present travail s'inscrit dans le cadre general des etudes consacrees a la protection pharmacologique du tissu cardiaque reperfuse apres une periode d'ischemie de courte duree. Les differentes etudes experimentales qui le constituent sont realisees sur un modele d'ischemie myocardique sur le cur isole et perfuse de rat, et prennent en compte une appreciation fonctionnelle, ultrastructurale et metabolique des effets du cycle ischemie-reperfusion. Une etude clinique, s'inscrivant dans une thematique voisine, complete l'ensemble. Dans la premiere partie de ce travail, nous avons mis en evidence l'implication des radicaux libres de l'oxygene, via la reaction de fenton, dans le developpement des lesions d'ischemie-reperfusion. Nous avons montre qu'une surcharge myocardique en fer augmentait la susceptibilite du tissu cardiaque vis a vis d'un cycle d'ischemie-reperfusion. En revanche, nous avons observe un effet benefique de la surcharge en fer sur l'incidence des troubles du rythme a la reperfusion. Enfin, nous avons montre qu'un traitement par des antioxydants et plus particulierement par l'euk8, molecule presentant in vitro une forte activite de type sod et catalase, entrainait une importante diminution des alterations fonctionnelles et ultrastructurales des curs surcharges en fer a la reperfusion. Dans la seconde partie, nous avons etudie le role des oligoelements (zn, cu, se et mn), cofacteurs d'enzymes de defense antiradicalaire, dans le developpement des lesions cellulaires associees a la reperfusion post-ischemique. Nous avons d'une part mis en evidence une plus grande vulnerabilite du tissu cardiaque dans les monocarences en oligoelements et plus particulierement dans les carences en selenium ou en cuivre. D'autre part, nous avons montre qu'un apport nutritionnel simultane en ces divers oligoelements augmentait l'activite des enzymes antioxydantes, limitant ainsi les consequences fonctionnelles et structurales de l'ischemie et de la reperfusion. Enfin, une troisieme partie consacree a l'etude de l'existence d'un stress radicalaire chez des patients presentant un infarctus du myocarde traite par thrombolyse, a permis de montrer 1) que les dosages plasmatiques des mda et de la gpx constituent un bon reflet de la production radicalaire apres traitement thrombolytique, et 2) que les systemes antioxydants physiologiques apparaissent modifies chez ces patients
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Marais, Erna. "Role of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and p38 mitogen activated protein kinase (p38 MAPK) in preconditioning of the ischaemic myocardium." Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53039.
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Thesis (PhD)--University of Stellenbosch, 2002.ENGLISH ABSTRACT: Ischaemic preconditioning (PC) is the phenomenon whereby a short episode of coronary occlusion followed by reperfusion protects the myocardium against a subsequent period of prolonged (also called index or sustained) ischaemia. Even though the exact mechanism of PC remains to be established, it implies that the heart has an endogenous protective mechanism against ischaemia which, if identified, may have important clinical implications. The importance of establishing the mechanism of PC lies in the potential to convert this biological phenomenon into a therapeutic modality to be used clinically. If mediated by certain components of a signal transduction pathway, such a goal will be achievable. Several triggers and signal transduction pathways have been implicated in the mechanism of protection induced by PC: for example, receptor-dependent endogenous triggers (such as adenosine and opioids) and receptor-independent endogenous triggers (such as free radicals and calcium). However, the involvement of both the ~-adrenergic signalling pathway as well as nitric oxide (NO) in PC has not been defined. It has been suggested that all triggers are linked to a common final pathway, for example, activation of protein kinase C (PKC) and/or the mitogen-activated kinases (MAPKs), in particular p38 MAPK. However, the role of the latter is still controversial. The aim of this study was to: (A) characterize changes in the cyclic nucleotides, cAMP and cGMP, and p38 MAPK occurring during the entire experimental procedure in an attempt to gain insights into the possible mechanisms involved in ischaemie PC (Chapter 3); (8) establish the significance of the changes observed in cAMP and cGMP by pharmacological manipulation of their respective pathways (Chapters 4 and 5); (C) establish the role of p38 MAPK in ischaemie PC: trigger or mediator involvement (Chapter 6). Isolated perfused working rat hearts were preconditioned by 3 x 5 min global ischaemia, interspersed by 5 min reperfusion, followed by 25 min global ischaemia and 30 min reperfusion. Functional recovery during reperfusion was used as end-point. Hearts were freeze-clamped at different times during the PC protocol, sustained ischaemia, as well as during reperfusion. Tissue cyclic nucleotides (cAMP and cGMP), cyclic nucleotide phosphodiesterase (cAMP- and cGMP-PDE) activities, adenylyl cyclase and protein kinase A activities and p-adrenergic receptor characteristics were determined. p38 MAPK activation was also assessed by Western blotting, using dual phospho-p38 MAPK (Thr180ITyr182) antibody as well as activating transcription factor 2 (ATF2) activation. In addition, to evaluate the role of p38 MAPK in PC protection, the effect of inhibition of p38 MAPK activation, by 8B203580, was determined in adult isolated rat cardiomyocytes as well as in isolated perfused rat hearts. Based on the results obtained, it is proposed that during a multi-cycle ischaemie PC protocol triggers (presumably endogenous catecholamines and NO) are released which induce cyclic changes in cyclic nucleotides, cAMP and cGMP. Both these cyclic nucleotides transiently activate the downstream stress kinase, p38 MAPK, which may trigger further downstream adaptive processes. Furthermore, the sustained ischaemic period of PC hearts was characterized by attenuated cAMP and elevated cGMP levels, as well as attenuated activation of p38 MAPK, which was associated with cardioprotection. In addition, pharmacological attenuation of p38 MAPK activation during sustained ischaemia led to functional recovery. It is concluded that the cardioprotection of PC is due to attenuation of ischaemia-induced p38 MAPK activation. Pharmacological manipulation of this kinase should be considered as a therapeutic modality in the future.
AFRIKAANSE OPSOMMING: Isgemiese prekondisionering (PK) verwys na die verskynsel waardeur 'n kort, verbygaande episode van isgemie gevolg deur herperfusie, die miokardium teen 'n daaropvolgende langdurige periode van isgemie beskerm. Die presiese meganisme van beskerming van PK moet nog opgeklaar word, maar dit impliseer dat die hart oor 'n endogene beskermingsmeganisme beskik wat, indien geïdentifiseer, belangrike kliniese implikasies mag hê. Die belang van opklaring van die meganisme van PK lê daarin dat 'n biologiese verskynsel in 'n terapeutiese modaliteit vir kliniese gebruik, omgeskakel kan word. Sou dit deur bepaalde komponente van 'n seintransduksiepad gemedieër word, is so 'n doel bereikbaar. Verskeie stimuli en seintransduksiepaaie is in PK betrokke: byvoorbeeld, reseptorafhanklike endogene stimuli (soos adenosien en opioïde), asook reseptor-onafhanklike endogene stimuli (soos vrye radikale en kalsium). Die betrokkenheid van die padrenerge seintransduksiepad asook stikstofoksied (NO) in PK egter nog nie behoorlik evalueer nie. Dit is voorgestel dat alle stimuli op 'n finale algemene pad uitloop, soos byvoorbeeld die aktivering van protein kinase C (PKC) en/of die mitogeen-geaktiveerde kinases (MAPKs), spesifiek die p38 MAPKs. Laasgenoemde se rol in PK is steeds kontroversieël. Die doel van die studie was dus: (A) karakterisering van die veranderinge in die sikliese nukleotiede, cAMP en cGMP, en p38 MAPK wat tydens die hele eksperimentele prosedure plaasvind, in 'n poging om meer insig te verkry aangaande moontlike meganismes betrokke in isgemiese PK (Hoofstuk 3); (8) bepaling van die belang van die waargenome veranderinge in cAMP en cGMP deur hulonderskeie paaie farmakologies te manipuleer (Hoofstukke 4 en 5); (C) bepaling van die rol van p38 MAPK in PK: betrokkenheid as stimulus of mediator (Hoofstuk 6). Geïsoleerde, geperfuseerde werkende rotharte is geprekondisioneer deur blootstelling aan 3 x 5 min globale isgemie, afgewissel met 5 min herperfusie, gevolg deur 25 min globale isgemie en 30 min herperfusie. Funksionele herstel tydens herperfusie is as eindpunt gebruik. Harte is op verskillende tye tydens die PK protokol, volgehoue isgemie, asook herperfusie gevriesklamp. Weefsel sikliese nukleotiede (cAMP en cGMP), die aktiwiteit van sikliese nukleotied fosfodiesterases (cAMP- en cGMP-PDE), adeniel siklase en protein kinase A (PKA) asook die eienskappe van die p-adrenerge reseptor is gemeet. p38 MAPK aktivering is met Westerse oordragtegnieke bepaal, deur van dubbel gefosforileerde p38 MAPK (Thr180fTyr182) antiliggame asook geaktiveerde transkripsie faktor 2 (ATF2) gebruik te maak. Die rol van p38 MAPK in PK beskerming is evalueer deur die effek van inhibisie van p38 MAPK aktivering met SB 203580, in volwasse geïsoleerde rot kardiomiosiete asook in geïsoleerde geperfuseerde rotharte, te bepaal. Na aanleiding van die resultate, is voorgestel dat, tydens 'n multi-siklus isgemie PK protokol, stimuli (moontlik endogene katekolamiene en NO) vrygestel word wat die sikliese veranderinge in sikliese nukleotiede, cAMP en cGMP, veroorsaak. Beide hierdie sikliese nukleotiede aktiveer die distale stres kinase, p38 MAPK, op 'n betekenisvolle, maar verbygaande manier. Hierdie kinase mag verdere distale aanpassingsprosesse stimuleer. Die volgehoue isgemiese periode van PK harte is gekenmerk deur verminderde cAMP en verhoogde cGMP vlakke, asook verminderde aktivering van p38 MAPK. Hierdie veranderinge is met beskerming van die hart teen isgemie geassosieer. Daarbenewens, farmakologiese vermindering van p38 MAPK aktivering tydens volgehoue isgemie het tot verbeterde funksionele herstel gelei. Die gevolgtrekking is gemaak dat die beskermende effek van PK die gevolg is van verminderde aktivering van isgemies-geïnduseerde p38 MAPK. Farmakologiese manipulasie van hierdie kinase moet in die toekoms as terapeutiese modaliteit oorweeg word.
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Garnier, Anne. "Le métabolisme énergétique du myocarde dans le préconditionnement ischémique : aspects cinétiques étudiés sur le coeur isolé de rat." Grenoble 1, 1995. http://www.theses.fr/1995GRE10225.
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Le preconditionnement ischemique (pci) decrit la situation au cours de laquelle le myocarde, soumis prealablement a un ou plusieurs episodes brefs d'ischemie-reperfusion, augmente sa tolerance a une ischemie ulterieure prolongee. Le role joue par les modifications du metabolisme energetique dans le determinisme de ce phenomene transitoire n'est pas encore clairement etabli. C'est dans cette perspective que s'inscrit ce travail sur le cur perfuse de rat. - l'ischemie de preconditionnement consiste en 3 min d'ischemie globale totale (ou 2 fois 3 min separees de 6 min) et l'ischemie prolongee (globale partielle de 25 min) est imposee 6 ou 12 min plus tard. - la caracterisation de la dynamique des contenus en composes phosphoryles (atp, phosphocreatine-pcr, phosphate inorganique-pi) et du ph intracellullaire est realisee par spectroscopie de rmn du p-31. Lorsque le pci est efficace, le myocarde presente des capacites contractiles residuelles augmentees a la reperfusion. Cette situation s'accompagne, lors de l'ischemie prolongee et de la reperfusion, d'un statut energetique plus eleve. L'analyse detaillee de la phase de pci met en evidence une production supranormale transitoire de pcr dont la duree de vie semble reliee au developpement de l'efficacite du pci. - la caracterisation de la mobilisation du glycogene fait apparaitre que l'efficacite du pci (1) n'est pas liee a l'erosion prealable de la reserve glycogenique et (2) est associee a une reduction de la glycogenolyse pendant l'ischemie prolongee, tout particulierement dans sa phase initiale, ou elle peut-etre expliquee par la diminution de l'activite de la glycogene-phosphorylase b. - le role eventuel des canaux potassiques modulables par l'atp (k#a#t#p) est envisage, car leur implication n'est pas clairement etablie dans le pci du cur de rat, en utilisant un antagoniste specifique (glibenclamide) et un agoniste hautement selectif (sr 47063). Si la seule activation prealable des canaux k#a#t#p fait apparaitre une cardioprotection nette, l'activation du canal k#a#t#p ne semble pas etre une composante majeure des mecanismes mis en uvre dans le pci. - certaines des modifications metaboliques associees au pci semblent donc participer au determinisme de son efficacite
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Harhous, Zeina. "Deciphering the Interlink between STAT3 and MAPKs in Ischemia/Reperfusion and Ischemic Conditioning." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1145.
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Les maladies cardiovasculaires sont une des principales causes de morbidité et de mortalité au monde. La plus courante est l’infarctus du myocarde définit pathologiquement par la mortalité cellulaire dû à une ischémie prolongée d’une partie du ventricule gauche. L'ischémie est caractérisée par un apport sanguin insuffisant causé par une obstruction d’une artère coronaire. La restauration, en clinique, du flux sanguin, appelée reperfusion, est considérée comme la méthode la plus efficace contre les dommages ischémiques. Paradoxalement, cette restauration du flux sanguin est associée à une exacerbation de la lésion tissulaire, entraînant alors des lésions d'ischémie-reperfusion (I/R). Dans le but de limiter ces lésions, le conditionnement ischémique myocardique est une avancée majeure dans le domaine de la cardioprotection. Ce protocole confère ses effets cardioprotecteurs via le recrutement de divers mécanismes endogènes suivant l’activation de deux voies intracellulaires : la voie RISK (Reperfusion Injury Salvage Kinase) et/ou la voie SAFE (Survivor Activator Factor Enhancer). Ces voies impliquent l'activation de différentes cascades de signalisation et de protéines kinases. En particulier, concernant la voie SAFE, le transducteur de signal et l'activateur de transcription-3 STAT3, a été identifié comme un acteur clé dans le postconditionnement ischémique (PostCI). Il est suggéré que les effets cardioprotecteurs attribués à STAT3 soient liés à ses effets en tant que facteur de transcription et en tant que régulateur de l’activité mitochondriale, mais tout n’est pas encore connu. En revanche, il est admis que STAT3 est activé par la phosphorylation ciblant les résidus tyrosine 705 et sérine 727. Dans nos travaux actuels, nous avions initialement pour objectif d’étudier les rôles cardioprotecteurs mitochondriaux de STAT3 après une I/R et un PostCI. Cependant, nous n'avons pas été en mesure de détecter STAT3 dans les mitochondries de cardiomyocytes adultes de souris, dans des conditions basales et de stress, en utilisant différentes approches. Fait intéressant, nous avons montré une localisation exclusive de STAT3 dans les myocytes cardiaques adultes, le long des tubules T, et nous avons mis en évidence les inconvénients des techniques précédemment utilisées.Outre les rôles putatifs de STAT3 dans les mitochondries, nous avons ciblé ses effets dans la signalisation et la génomique au cours de l'I/R et du PostCI. Nous avons tout d’abord cherché à déterminer, pendant l’I/R et le PostCI, la cinétique temporelle d’activation de STAT3 et des autres kinases de la voie RISK, notamment Akt et les MAPK ERK1 / 2, JNK et p38. En outre, nous avions pour objectif d’étudier les liens entre les voies SAFE et RISK en déchiffrant les liens entre STAT3 et les kinases RISK au cours du PostCI. Nous avons montré qu’après une ischémie et un temps court de reperfusion, STAT3 et ERK1/2 sont activés, et que l’utilisation d’un PostCI active d’autant plus STAT3 en induisant exclusivement la phosphorylation de sa tyrosine. Nous avons également montré que l’interconnexion entre les voies SAFE et RISK, dans le protocole PostCI utilisé, se fait par STAT3 et ERK1/2. À partir de ces résultats, nous nous sommes dirigés vers la génomique grâce à laquelle nous avons étudié l'activité de STAT3 au cours de l'IPoC. À cet égard, nous avons montré que STAT3 est impliqué dans la régulation de la réponse inflammatoire au cours de la PostCI. Dans l’ensemble, cette étude présente une approche globale des fonctions mitochondriales, de signalisation et génomiques de STAT3 dans le contexte de la protection cardiaqueCardiovascular diseases are leading causes of morbidity and mortality worldwide. Among the mostly prevailing cardiovascular diseases is myocardial infarction, which is pathologically defined as myocardial death due to a prolonged ischemia. Ischemia is an insufficient supply of blood caused by a blockade in the coronary arteries. The early restoration of blood flow is considered the most effective method against the ischemic lesions. Paradoxically, this blood flow restoration is associated with an exacerbation of the tissue injury, leading to the ischemia-reperfusion (I/R) injury. To avoid this injury, the myocardial ischemic conditioning protocol has rejuvenated the field of cardioprotection. This protocol confers its cardioprotective effects via recruiting various endogenous mechanisms following the activation of two intracellular pathways: the reperfusion injury salvage kinase (RISK) or survivor activator factor enhancer (SAFE) pathways. These pathways involve the activation of different signaling cascades and protein kinases. Zooming in through the SAFE pathway, the signal transducer and activator of transcription-3, STAT3, has been identified as a prominent key player in ischemic postconditioning (IPoC). The cardioprotective effects attributed to STAT3 are suggested to be linked to its roles as a transcription factor and as a regulator of the mitochondrial activity, but these are not well studied and elaborated. STAT3 is activated by phosphorylation, which targets the tyrosine 705 and serine 727 residues. In our current work, we initially aimed to investigate the mitochondrial cardioprotective roles of STAT3 following I/R and IPoC. However, we were not able to detect STAT3 in the mitochondria of adult mouse cardiomyocytes under variousbasal and stress conditions using different approaches. Interestingly, we showed an exclusive STAT3 pattern in adult cardiac myocytes, along the T-tubules, and highlighted drawbacks of previously used techniques. Aside from the mitochondrial roles of STAT3, we targeted its signaling and genomic roles during I/R and IPoC. We first aimed to determine, during I/R and IPoC, the temporal kinetics of activation of STAT3 and the other kinases of the RISK pathway including Akt and the MAPKs ERK1/2, JNK and p38. In addition, we aimed to decipher the interlink between the SAFE and RISK pathways through deciphering the interlink between STAT3 and the RISK kinases following IPoC. We showed that a short reperfusion time activates STAT3 and ERK1/2 following ischemia, and that the application of IPoC further activates STAT3 through inducing its tyrosine phosphorylation. We also showed that the interlink between SAFE and RISK pathways, in the IPoC protocol we used, is through STAT3 and ERK1/2. From this signaling level, we moved toward the genomic level whereby we investigated the genomic activity of STAT3 during IPoC. In this regard, we have shown that STAT3 is involved in the regulation of the inflammatory response during IPoC. Overall, this study presents a global approach of STAT3’s mitochondrial, signaling and genomic functions in the context of cardiac protection
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FRANCO, Leandro Guimarães. "ANESTESIA COM CETAMINA S(+) ASSOCIADA À ATROPINA E XILAZINA EM CÃES: AVALIAÇÃO CARDÍACA E BIOQUÍMICA SÉRICA." Universidade Federal de Goiás, 2008. http://repositorio.bc.ufg.br/tede/handle/tde/895.
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Previous issue date: 2008-03-05Changes in physiological parameters of electrocardiography, echocardiography and biochemistry markers were evaluated in dogs anesthetized with different associations of atropine, xylazine and S-ketamine. Twenty three healthy female dogs randomly distributed in four groups named as GI-6, GII-6, GIII-6 and GIV-5 were treated respectively with atropine and S-ketamine (0,04mg/kg; 10 mg/kg); S-ketamine (10 mg/kg); atropine, xylazine and S-ketamine (0,04mg/kg; 1,1 mg/kg; 10 mg/kg) and xylazine and S-ketamine (1,1 mg/kg; 10 mg/kg). Ten minutes after induction, 5mg/kg of S-ketamine was administered to animals from all groups. Measurements of electrocardiogram, echocardiogram and serum activity of aspartate aminotransferase (AST), creatine kinase (CK) and creatine kinase MB isoenzyme (CK-MB) were evaluated for 36 hours. Concerned to electrocardiography, the proposed anesthetic protocols showed significant changes especially in atrioventricular conduction period (PR interval) and systole period (QT interval), mostly in GIV. In relation to echocardiography, the main alterations happened in following variables, final stroke volume, ejection fraction and cardiac output, predominantly in GIV. In serum biochemistry analysis, it was observed alterations in CK and CK-MB values in all groups, which maintained changed for a longer time in GIII and GIV. Thus, under conditions of this study, it can be conclude that atropine, xylazine and S-ketamine association (GIII) determined lower effects on heart, while marking alterations occurred in animals from GIV
Avaliaram-se as alterações eletrocardiográficas, ecocardiográficas e de marcadores bioquímicos em cadelas anestesiadas com atropina-xilazina-cetamina-S (+) em diferentes associações. Utilizaram-se 23 cadelas, clinicamente saudáveis, distribuídas aleatoriamente em quatro grupos experimentais (GI-n=6, GII-n=6, GIII-n=6 e GIV-n=5). Os animais do GI, GII, GIII e GIV foram tratados respectivamente com atropina-cetamina-S (+) (0,04 mg/kg 10 mg/kg), cetamina-S (+) (10 mg/kg), atropina-xilazina-cetamina-S (+) (0,04mg/kg 1,1 mg/kg -10 mg/kg) e xilazina-cetamina-S (+) (1,1 mg/kg -10 mg/kg). Após dez minutos da aplicação da indução, foram reaplicados 5,0 mg/kg de cetamina-S (+) nos animais de ambos os grupos. Avaliaram-se os animais por um período de 36 horas, por meio de eletrocardiograma, ecocardiograma e avaliações da atividade sérica de aspartatoaminotransferase (AST), creatinoquinase (CK) e creatinoquinase fração-MB (CK-MB). Relativamente à eletrocardiografia, os protocolos anestésicos estudados desencadearam mudanças significativas especialmente no tempo de condução atrioventricular, evidenciado pelo aumento da duração do intervalo PR, e período de sístole, evidenciado pelo aumento da duração do intervalo QT, sugerindo um quadro de sobrecarga ventricular, predominantemente evidenciados nos animais do grupo tratado com a associação xilazina-cetamina-S (+). Quanto à avaliação ecocardiográfica, as principais alterações foram evidenciadas entre as variáveis, volume sistólico final, fração de ejeção e débito cardíaco, predominantemente nos animais xilazina-cetamina-S (+). Com relação à avaliação bioquímica, notou-se que independente do tratamento adotado foram observadas alterações nos valores de CK e CK-MB, permanecendo alteradas por um período maior nos animais dos grupos tratados com atropina-xilazina-cetamina-S(+) ou xilazina-cetamina-S (+). Desse modo, diante das condições em que o estudo foi realizado permite-se concluir que dentre os grupos estudados, a associação atropina-xilazina-cetamina-S (+) desencadeou menores efeitos sobre o coração, enquanto que as alterações mais significativas ocorreram nos animais tratados com xilazina-cetamina-S(+)
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Segawa, Daisuke. "Time dependency in the protection from myocardial injury after myocardial ischemia and reperfusion : new insights from experimental studies with the ultrashort-acting calcium antagonist clevidipine /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-141-1.
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Abunasra, Haitham Juma. "Gene therapy in myocardial ischemia-reperfusion." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404964.
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Rahmouni, Hidayat. "Stress oxydant et sensibilisation à l'ischémie/reperfusion myocardique dans le syndrome métabolique et le diabète chez le rat. Evaluation de l'apport de composés antioxydants et à visée antidiabétique, naturels ou de synthèse." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4795.
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Les complications cardiovasculaires au décours du syndrome métabolique ou le diabète, sont une conséquence directe de l'installation d'un stress oxydant, dont la progression est associée à une augmentation de la production de radicaux libres et des composés de dégradation des molécules biologiques, parallèlement à une diminution des défenses antioxydantes. Ces pathologies, enjeux important de santé publique, suscitent la recherche de méthodes de prévention ou de traitement. Dans ce contexte notre 1er objectif a été de développer deux modèles chez le rat, mimant les conditions du syndrome métabolique et du diabète, le premier par administration d'un régime ou d'une boisson riches en fructose, le deuxième étant induit par voie chimique. Notre 2ème objectif a été de préparer des extraits riches en phycocyanines d'un antioxydant naturel, la spiruline, et de les évaluer dans ces deux modèles expérimentaux. Les résultats ont montré l'effet bénéfique de la spiruline sur la diminution de la glycémie, l'amélioration de l'insulinémie et du profil lipidique, ainsi que sur le renforcement des défenses antioxydantes et l'amélioration de la récupération fonctionnelle du myocarde après ischémie/reperfusion. Notre 3ème objectif a été de d'évaluer la capacité antioxydante et cardioprotectrice de nouveaux dérivés polyphénoliques. Une trentaine de nouveaux flavonols ont été isolés au Laboratoire, les meilleurs résultats ont été obtenus avec ceux portant un groupement ionisable en C6, et des groupements méthoxy en C3' et C5', apportant une meilleure solubilité et une plus faible cytotoxicitéCardiovascular disorders related to metabolic syndrome or diabetes are a direct consequence of the installation of oxidative stress, which progress is associated with free radicals overproduction and increase of biomolecules degradation, in parallel with lowered antioxidant defenses. These pathologies represent a considerable public health problem, and research to improve prevention and treatment is strongly encouraged. In this context, our 1st objective was to develop two models in vivo, mimicking on rats metabolic syndrome and diabetes conditions, one by administration of a fructose-enriched diet or drink, the second being chemically induced. Our 2nd objective was to prepare phycocyanine-rich extracts of spirulina, a natural antioxidant, and to evaluate their properties on the two experimental animal models. Results showed the beneficial effect of spirulina on glycemia decrease, insulinemia improvement and lipid profile, accompanied by and increase of the antioxidant defenses and an improvement of myocardial functional recovery after ischaemia/reperfusion. Our 3rd objective was of to evaluate the antioxidant and cardioprotective capacities of new polyphenol derivatives. Around thirty new flavonols have been isolated in our Laboratory; best results were obtained with molecules bearing an ionizable group in C6 position, and methoxy groups in C3' and C5', leading to better solubility and lower cytotoxicity. Finally, the 4th objective was to quantify the therapeutic and cardioprotective potential of hybrid compounds, associating an antioxidant pattern with an antidiabetic molecule
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McDonough, Jason L. "Myofilament protein modifications in myocardial ischemia/reperfusion." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ65682.pdf.
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Roekaerts, Paul M. H. J. "Alpha2-adrenergic receptor agonists in myocardial ischemia." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1997. http://arno.unimaas.nl/show.cgi?fid=5784.
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Betti, Roberto Tadeu Barcellos. "Efeito da repaglinida sobre o pré-condicionamento isquêmico." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-02082007-103820/.
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Introdução: O aumento da tolerância do miocárdio isquêmico observado durante o segundo de dois testes de esforços seqüenciais, o fenômeno do pré-aquecimento, foi proposto como um modelo clínico do pré-condicionamento isquêmico. Bloqueadores dos canais de K-ATP dependentes, tais como as sulfoniluréias, podem induzir a perda do pré-condicionamento isquêmico, o qual poderia estar envolvido no aumento dos eventos cardiovasculares. A repaglinida é um agente hipoglicemiante oral, pertencente à família da meglitinida e supostamente dotada de menor efeito no pré-condicionamento isquêmico, ainda que o fármaco tenha seu principal mecanismo de ação nos canais de K-ATP dependentes. Objetivos e Métodos: O objetivo foi investigar os efeitos da repaglinida no fenômeno do pré-condicionamento isquêmico em pacientes diabéticos com doença coronariana estável. Foram estudados 42 pacientes diabéticos tipo 2, com angina estável e doença arterial documentada. Todos os pacientes tinham testes ergométricos positivos para isquemia. Na primeira fase do teste, a sulfoniluréia e os betabloqueadores foram suspensos por trinta dias e sete dias, respectivamente. Os pacientes foram submetidos a dois testes ergométricos seqüenciais, com intervalo de trinta minutos (testes 1 e 2). Na segunda fase, os pacientes receberam repaglinida por sete dias e mais dois testes ergométricos foram repetidos (testes 3 e 4). Resultados: Todos os pacientes alcançaram ST >1 mm na primeira fase (Teste 1 e 2). O tempo alcançado no teste 2 foi maior que aquele alcançado no teste 1 (4:44s. x 5:37s. p=0,001), como também foi maior a duração do exercício (6:15s x 6:29s. p=0,008), denotando pré-condicionamento isquêmico. Após o uso da repaglinida, nos testes 3 e 4, observou-se menor tempo alcançado para atingir isquemia no teste 4 (5:37s. x 4:58s. p=0,001). Observou-se, ainda, menor tempo de tolerância ao exercício na fase 2 (6:57s x 6:34s. p=0,007). Em relação ao surgimento de angina, não se constataram diferenças estatísticas entre as duas fases. Conclusão: Nos pacientes diabéticos com doença coronariana estável, a repaglinida bloqueou o pré-condicionamento isquêmico.Background: The increase of tolerance to myocardial ischemia observed during the second of two sequential exercise tests, the warm-up phenomenon, has been proposed as a clinical model of ischemic preconditioning. Blockers of K-ATP channels, such as the Sulfonylurea drugs, can induce loss of ischemic preconditioning, what could be involved in an increase of cardiac events. Repaglinide is a hypoglycemic agent with supposedly lower influence on ischemic preconditioning, despite acting in K-ATP channels. Objectives and Methods: This study investigated the effects of repaglinide on the ischemic preconditioning in diabetic patients with CAD. There were 42 patients and inclusion criteria were positive treadmill test for myocardial ischemia. Sulphonylureas and beta-blocking agents were withdrawn 30 and 7 days respectively before phase 1 of the study. In this phase, the patients underwent two consecutive treadmill exercise tests at 30 minute intervals (test 1 and test 2). In phase 2 of the study, all patients received repaglinide 2 mg three times daily during 7 days before treadmill exercise test (test 3 and test 4). Results: All patients achieved 1.0 mm ST-segment depression during phase 1. The time achieved to ST depression during test 2 was greater than that during test 1 (4:44s vs. 5:37s. p=0.001) as well as the duration of the exercise (6:15s vs.6: 29s. p=0.008), suggesting a higher ischemic threshold. In phase 2 after repaglinide, all patients achieved 1 mm ST-segment depression. However, the time achieved to ST depression, as well as the duration of the exercise, was lower in test 4 comparing with test 3. There were no statistical differences regarding angina episodes in phase 1 or phase 2. Conclusions: In diabetic patients with stable coronary disease, the oral hypoglycemic agent repaglinide abolished the myocardial ischemic preconditioning.
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SAKAMOTO, NOBUO, TATSUAKI MATSUBARA, YOSHIHIRO KAKINUMA, and TATSUO HASHIMOTO. "MYOCARDIAL METABOLIC MARKERS OF TOTAL ISCHEMIA IN VITRO." Nagoya University School of Medicine, 1994. http://hdl.handle.net/2237/15927.
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Ghormley, Michael Roger. "Psychosocial factors in mental stress induced myocardial ischemia /." Digital version accessible at:, 2000. http://wwwlib.umi.com/cr/utexas/main.
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Qi, Zhao. "INFLAMMATORY PROTEASES AND CARDIAC REPAIR POST MYOCARDIAL ISCHEMIA." Master's thesis, Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/216601.
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PhysiologyM.S.
Neutrophils are thought to orchestrate myocardial remodeling during the early progression to cardiac failure through the release of reactive oxygen species, antimicrobial peptides, and proteases. Although neutrophil activation may be beneficial at early stages of disease, excessive neutrophil infiltration detrimentally leads to cardiomyocyte death and tissue damage. The neutrophil-derived serine protease cathepsin G (CG) has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis1. However the role of inflammatory serine proteases in cardiac remodeling and cardiac regeneration in-vivo is still unknown. We showed that cardiac injection of neutrophil derived protease led to early cardiac dilatation and dysfunction characterized by an increase in matrix metalloprotease (MMP) activation and extracellular matrix degradation along with an increase in myocyte death by apoptosis. To assess the role of these serine proteases, we used mice lacking dipeptidyl peptidase I (DPPI), an enzyme involved in major inflammatory protease activation. DPPI deficient mice demonstrated a more robust functional recovery after ischemia reperfusion (IR) and myocardial infarction (MI) injury, as well as significantly reduced myocyte apoptosis, cardiac dilatation, infarct size and mortality rate. Meanwhile, our data showed increased groups of cardiac stem cells and proliferating cardiac cells in the MI 7-days DPPI knockout mice. We also found enhanced DPPI expression in response to pathological stress stimuli in mice. These findings reveal an unrecognized role of DPPI as a key mediator of post-ischemia cardiac injury and show that inflammatory derived proteases may contribute to the pathological cardiac remodeling and cardiac regeneration, and may be considered as novel target for future therapies.
Temple University--Theses
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Hussain, Shazia Tanvir. "Invasive and non-invasive indices of myocardial ischemia." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/invasive-and-noninvasive-indices-of-myocardial-ischemia(e8050a58-2a0e-4b05-804c-a2cd5d22e37b).html.
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Recent guidelines for the management of stable coronary artery disease (CAD) and myocardial revascularisation emphasise the importance of the presence of ischaemia for guiding revascularisation. Cardiovascular Magnetic Resonance (CMR) perfusion imaging and fractional flow reserve (FFR) are two methods of physiological ischaemia assessment, one invasive and the other non-invasive. In order that the results are interpreted accurately, it is important to be aware of the limitations and advantages of each technique. These techniques measure different parameters so it is not uncommon that the two tests may lead to differing results in one patient. In addition, the extent and not just the presence of ischaemia are increasingly considered to be an important variable that needs to be considered. The aim of this thesis is to assess the similarities and differences in ischaemia assessment between the two tests, in particular in the assessment of ischaemic burden and also on specific clinical scenarios such as microvascular and multivessel disease. Firstly, a close correlation between the extent of ischaemia measured by CMR and the FFR value itself is demonstrated. FFR measurement has previously been used as an indicator of the presence of ischaemia alone and the relationship with ischaemic extent has never been proven. It is an interesting finding, which lends weight to the strategy of targeted revascularisation aiming for the greatest reduction in ischaemic burden. The FFR value itself as an indicator of ischaemic burden is also useful in centres that do not have access to sophisticated imaging techniques such as CMR. Secondly, another simple method of invasive estimation of ischaemic burden is demonstrated via the use of a functional jeopardy score. This is validated against CMR but is limited by a tendency to overestimate the extent of ischaemia. The use of the FFR value itself, as demonstrated in chapter 4, therefore offers better potential as a marker of ischaemic extent. Two examples of areas where there may be discrepant results are in patients with multivessel disease and patients with microvascular disease. A comparative analysis of the diagnostic accuracy of these two tests in multivessel disease demonstrates reasonable concordance but does lead us to question which test is the diagnostic reference standard. In the discrepant cases, it is unclear whether CMR underestimates or FFR overestimates the number of perfusion territories. Finally, a novel method of non invasively differentiating between multivessel disease and microvascular disease is demonstrated, providing a feasible solution to this diagnostic dilemma. Multivessel CAD and microvascular disease can be accurately distinguished using the novel concept of perfusion dephasing analysis, which analyses the spatio-temporal variability in the distribution of myocardial perfusion to the LV myocardium. An improved diagnostic algorithm of CMR is therefore proposed, including the analysis of the variance of time to peak signal intensity, the most accurate index for perfusion dephasing. This has the potential for patient benefit in the reduction of unnecessary invasive angiography procedures.
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Sadigh, Bita. "Analgetic and algetic effects of adenosine in healthy volunteers and patients with coronary artery disease /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-382-5/.
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Réant, Patricia. "Analyse échocardiographique des déformations myocardiques en speckle tracking." Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21662/document.
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L’analyse de la fonction systolique en échocardiographie représente un challenge majeur depuis une vingtaine d’années dans le but d’améliorer la détection et la quantification des anomalies de la contraction myocardique. L’analyse des déformations myocardiques consiste à étudier le pourcentage d’étirement ou de raccourcissement myocardiques au cours du cycle cardiaque. Après le grand pas en avant dans ce domaine, consécutif à l’avènement du Doppler tissulaire il y a un quinzaine d’années, ces 4 dernières années ont vu naître une nouvelle technique d’analyse bidimensionnelle des déformations, porteuse de grands espoirs car s’affranchissant de la limitation liée à l’angle d’incidence Doppler et basée sur le suivi des marqueurs acoustiques de la paroi myocardique : le « speckle tracking echocardiography » ou « 2D strain ». Cette thèse rapporte tout d’abord une série de travaux orientés sur la validation de ce nouvel outil. Nous avons ensuite appliqué expérimentalement cette technique pour évaluer sa capacité à détecter l’ischémie myocardique lors d’un examen de stress sous dobutamine en comparaison à l’analyse de perfusion myocardique en échographie de contraste. Enfin, nous exposons plusieurs expériences cliniques qui témoignent de quelques applications potentielles de cette technique dans la prise en charge des patients porteurs de cardiopathies diverses : myocardiopathie hypertrophique, fibrillation auriculaire paroxystique et recherche de viabilité sous faibles doses de dobutamine chez les patients porteurs d’une cardiopathie ischémiqueFor 20 years, analysis of systolic myocardial function by echocardiography is a major challenge to improve the detection and the quantification of myocardial contractility abnormalities. The principle of myocardial deformation analysis consists in evaluating the percentage of myocardial thickening or shortening during the cardiac cycle. After a big step forward with the advent of tissue Doppler imaging for 15 years, the 4 last years have seen the apparition of a new technique of bidimensional analysis, without angle dependency, based on the tracking of the acoustic markers of the myocardial wall, and called « speckle tracking echocardiography » or « 2D strain ». This thesis reports serial studies oriented on the validation of this new tool and on the experimental application of this technique in the detection of myocardial ischemia during pharmacological dobutamine stress echocardiography, in comparison with myocardial perfusion analysis by contrast echocardiography. Finally, we report some clinical experiences using the speckle tracking echocardiography which attest of some clinical potential applications of this technique in the management of the patients with different cardiomyopathies: hypertrophic cardiomyopathy, lone paroxysmal atrial fibrillation, and analysis of myocardial regional deformation during low doses dobutamine infusion to investigate viability in patients with ischemic cardiomyopathy
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PAYAN, PHILIP. "L'ischemie myocardique silencieuse : a propos de douze observations." Toulouse 3, 1989. http://www.theses.fr/1989TOU31025.
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Maret, Eva. "Noninvasive Evaluation of Myocardial Ischemia and Left Ventricular Function." Doctoral thesis, Linköpings universitet, Klinisk fysiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-18315.
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The general aim of this thesis was, following the path of the ischemic cascade, to evaluate the feasibility of some new non-invasive techniques for the detection of myocardial ischemia, the extent of infarcted myocardium, and for the quantification of systolic left ventricular function. Reduced longitudinal myocardial velocity and displacement may be early signs of ischemia. We evaluated the diagnostic sensitivity and specificity of pulsed tissue Doppler for the detection of ischemia and scar during dobutamine stress testing and compared it with myocardial perfusion scintigraphy (SPECT) in patients with a history of unstable angina. Pulsed tissue Doppler was useful for objective quantification of left ventricular longitudinal shortening and for differentiation between patients with a normal, ischemic or necrotic myocardium. The coronary flow velocity reserve (CFVR) of the left anterior descending artery (LAD) was studied with transthoracic Doppler echocardiography (TTDE) during adenosine stress. Patients with a clinical suspicion of stress induced myocardial ischemia were investigated, and the results were compared with the findings from SPECT. A CFVR >2 in the LAD could exclude significant coronary artery disease in a clinical setting, however, in cases with low CFVR, multiple cardiovascular and metabolic risk factors as well as epicardial coronary artery disease or microvascular dysfunction might be responsible. TTDE is a promising tool, e.g. for follow-up after coronary interventions or for evaluating endothelial function over time. A third study focused on the importance of accurate and reproducible measurements of left ventricular volumes and ejection fraction (LVEF). Patients with known or suspected coronary artery disease with different levels of LVEF were enrolled. We compared the LVEF determined with an automatic echocardiographic method with manual planimetry, visual assessment of LVEF and with quantitative myocardial gated SPECT. The software using learned pattern recognition and artificial intelligence (AutoEF) applied on biplane apical echocardiographic views reduced the variation in measurements without increasing the time required. The method seems to be able to reduce variation in the assessment of LVEF in clinical patients, especially for less experienced readers. We evaluated a new feature tracking software for its ability to detect infarcted myocardium on cine-MR images. Patients were selected based on the presence or absence of myocardial scar in the perfusion area of the LAD. The software tracked myocardial wall motion and allowed the calculation of velocity, displacement and strain in radial and longitudinal directions. Feature tracking of cine-MR images detected scar segments with transmurality >50% within the distribution of the LAD with 80% sensitivity and 86% specificity (radial strain), without the need for the administration of gadolinium-based contrast. In summary, we have evaluated some of the noninvasive techniques in the wide array of diagnostic tools available for the diagnosis of ischemic heart disease. Their availability, low costs, freedom from radiation and repeatability are essential as well as their diagnostic ability.
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Yazdanpanah, Mehrdad. "Pyruvate improves myocardial functional recovery after ischemia and reperfusion." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/MQ34078.pdf.
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Zwaan, Christoffel de. "Recognition of high risk patients with acute myocardial ischemia." [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1989. http://arno.unimaas.nl/show.cgi?fid=5453.
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Brown, David Avery. "Myocardial ATP-sensitive potassium channels and ischemia/reperfusion injury." Diss., Connect to online resource, 2005. http://wwwlib.umi.com/cr/colorado/fullcit?p3190363.
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Meintjes, André F. (André Francois). "Autonomic Reflexes of the Heart During Acute Myocardial Ischemia." Thesis, University of North Texas, 1993. https://digital.library.unt.edu/ark:/67531/metadc279150/.
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This study investigated whether acute myocardial ischemia of the anterior left ventricular wall induced an increase in cardiac sympathetic efferent nerve activity and thereby affected regional myocardial blood flow and contractile function.
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Yamamoto, Setsuko. "Studies on the Na[+]/H[+] exchange in myocardial ischemia." 京都大学 (Kyoto University), 2002. http://hdl.handle.net/2433/150305.
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Bousette, Nicolas. "Thermal injury increases TMR induced angiogenesis in the ischemic myocardium." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31198.
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Background. A growing number of patients suffering from ischemic cardiomyopathy are not eligible for conventional revascularization. This has prompted new research in the field of angiogenesis. This study hypothesized that since inflammation is probably the mechanism behind TMR induced angiogenesis; a larger inflammatory response induced by thermal injury may lead to increased angiogenesis.Methods. The model used for this study was coronary artery ligation in the Rat. Four groups of animals were used to compare the novel experimental approach with conventional TMR and with ischemia alone. Neovascularization was determined by immunohistochemical techniques using anti-Factor VIII antibody. Evaluation of VEGF, Ang-1 and Ang-2 expression was also carried out using immunohistochemistry.
Results. The experimental "HOT" TMR technique resulted in significantly increased angiogenesis presumably due to the thermal injury induced by the novel technique. Also a significant increase in VEGF expression was observed in all ischemic groups. Ang-1 expression was decreased in the experimental group while it was similar in the other groups. Finally Ang-2 was induced by ischemia as evidenced by increased expression among all ischemic groups. However Ang-2 expression did not significantly vary among ischemic groups.
Conclusions. The addition of thermal injury by heating of the needle led to an increased angiogenic response compared to ischemia alone and compared to conventional TMR. This increased angiogenesis was associated with increased VEGF expression at one week, however there was a significant inverse correlation between VEGF expression and angiogenesis among the ischemic groups. Also angiopoietin expression was in agreement with expression characteristics described in the literature.
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Diaz, Roberto Jose. "Ischemic preconditioning of the myocardium, role of angiotensin II receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0006/MQ28785.pdf.
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Ford, Meredith Katherine. "Ischemic preconditioning of the myocardium, role of protein tyrosine kinases." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0022/MQ40863.pdf.
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Mohammed, Salman Afroze Azmi. "Modulation of myocardium repair after ischemic injury : role of macrophages." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580134.
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Macrophages are primary responders that are involved in regulation of left ventricular remodeling post myocardial infarct (MI) at various levels. Macrophage role post ischemia can be best studied by eliminating or blocking their population and also by increasing their numbers, and determining the outcome. Four different approaches to modulate macrophage number or activity have been used: a) human diphtheria toxin receptor (hDTR) transgenic mice; b) injection with clodronate liposomes (CL) in C57 mice; c) pharmacologic blockade of TLR4 which is expressed also in macrophages; d) selection of Ml or inflammatory macrophages, by adoptive transfer of NF-kB P50-/- bone marrow (BM).
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Pandey, Raghav. "MicroRNA Mediated Proliferation of Adult Cardiomyocytes to Regenerate Ischemic Myocardium." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124343198575.
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Yamasaki, Kenzou. "Preconditioning with 15-min ischemia extends myocardial infarct size after subsequent 30-min ischemia in rabbits." Kyoto University, 1997. http://hdl.handle.net/2433/202231.
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