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Adedoyin, Oreoluwa O. "MECHANISMS OF CYCLOOXYGENASE-2-DEPENDENT HUMAN AORTIC SMOOTH MUSCLE CELL PHENOTYPIC MODULATION." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/34.
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Abdominal aortic aneurysm (AAA) is a disease of the aorta characterized by pathological remodeling and progressive weakening of the vessel resulting in the increased risk of rupture and sudden death. In a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, progression of AAAs is associated with reduced differentiation of smooth muscle cells (SMCs) at the site of lesion development. In the mouse model, the effectiveness of cyclooxygenase-2 (COX-2) inhibition for attenuating AAA progression is associated with maintenance of a differentiated SMC phenotype. However, the safety of COX-2 inhibitors is currently in question due to the increased risk of adverse cardiovascular events. Thus, it is crucial to identify mediators downstream of COX-2 that may provide new targets for treatment of this disease.
Recent studies in humans and mouse models have suggested that the microsomal prostaglandin E synthase (mPGES-1) enzyme, which acts downstream of COX-2, may also be involved in the pathogenesis of the disease. We hypothesized that increased prostaglandin E2 (PGE2) synthesis resulting from the induction of both COX-2 and mPGES-1 may result in reduced differentiation of SMCs, and that disruption of this pathway would preserve the differentiated phenotype. To test this hypothesis, human aortic smooth muscle cells (hASMCs) were utilized to examine the effects of a variety of agents involved in AAA development and the COX-2 pathway.
My findings suggest that one of the effects of exposing hASMCs to AngII involves a specific induction of mPGES-1 expression. Furthermore, although different COX-2-derived products may have opposing effects, mPGES-1-derived PGE2 may be the primary prostanoid synthesized by SMCs which functions to attenuate differentiation. Therefore, mPGES-1 inhibition may provide inhibition of PGE2 that is more specific than COX-2 inhibitor treatment and may serve as a therapeutic target for attenuating AAA progression by maintaining a differentiated SMC phenotype.
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MURAKAMI, Ryuichiro, Fukushi KAMBE, Hirohito MITSUYAMA, Kenji OKUMURA, Satoru NIWATA, Ryohei YAMAMOTO, and Hisao SEO. "Effect of Epidermal Growth Factor and Cyclosporin A on InterIeukin-8 Gene Expression in Human Aortic Smooth Muscle Cells." Research Institute of Environmental Medicine, Nagoya University, 2002. http://hdl.handle.net/2237/2781.
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Simmers, Phillip Charles. "Benefits of Nitric Oxide Cues to Matrix Synthesis by Healthy and Aneurysmal Human Smooth Muscle Cells within 3D Cocultures." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1399977973.
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Jagadesham, Vamshi Pulloori. "NK cell mediated lysis of vascular smooth muscle cells in abdominal aortic aneurysms." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578645.
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Abdominal aortic aneurysms (AAA) are characterised by a chronic inflammatory infiltrate within the abdominal aortic wall and aortic smooth muscle cell (AoSMC) apoptosis. It is postulated that the inflammatory infiltrate causes AoSMC apoptosis, with resultant aortic wall weakening and aneurysmal degeneration. This putative immune-mediated reaction against aortic wall component suggests that AAA may have features of an auto immune disease. It has been previously demonstrated that natural killer (NK) cells are elevated in the peripheral blood (PB) of AAA patients and display increased cytotoxicity against AoSMC. This study aimed to identify the molecular basis of the increased NK cell cytotoxicity and why an immune-mediated reaction occurs against AoSMC. Using multi-parametric flow cytometry (FC), expression of the activatory receptors NKp30, NKp44, NKp46 and NKG2D were analysed on PB NK cells from AAA patients and age-sex-matched healthy controls. No difference in activatory receptor expression or cell surface density (ΔMFI) existed between the two groups. Region specific (intra-luminal blood and AAA tissue) activatory receptor phenotypes were also investigated in AAA patients. The significant finding was a reduction in the ΔMFI of NKG2D on tissue NK cells, suggesting an interaction between this receptor and potential cognate ligands within the aortic wall. Characterised AoSMC explanted from AAA tissue were subjected to analysis using qRT-PCR and FC to identify the expression of death receptors (Fas, TRAIL-RI and TRAIL R2) and NKG2D ligands (MICA, MICB, ULBPI-3). AoSMC expressed mRNA for all NKG2D ligands. FC confirmed the cell-surface expression of NKG2D ligands and the death receptors. A significantly greater percentage of NK cells from AAA patients were CD107a+ when co-cultured with AAA AoSMC, thus accounting for the increased cytotoxicity in this group. Despite using anti-NKG2D it was not possible to inhibit NK cell degranulation in response to the NKG2D ligands on AoSMC. This work has demonstrated that AoSMC from AAA express death receptors and NKG2D ligands, potentially accounting for the NK cell molecular mechanism that leads to AoSMC apoptosis. The expression of NKG2D ligands, which have been demonstrated in other auto immune diseases, favours the hypothesis that AAA are an immune-mediated process directed against the abdominal aortic wall.
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Rowe, Daniel Thomas David. "Calcium stores and human vascular smooth muscle cell proliferation." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392964.
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Kemp, Christian R. W. "Mechanical influences on human vascular smooth muscle cell growth." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29397.
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The leading cause of death in Western countries is cardiovascular disease with over 1 million people dying each year as a result in the United States alone. One condition identified as a risk factor for cardiovascular disease is an increased blood pressure or "hypertension" which has been shown to result in morphological changes in blood vessels at different sites around the body, including narrowing of pre-capillary "resistance" vessels. This thesis has sought to investigate whether or not this narrowing of resistance vessels might result from the increased physical forces of hypertension exerted upon the vascular smooth muscle cells of the vessel wall and to investigate the intracellular signalling mechanisms initiating this cellular response. Results indicate that cultured human vascular smooth muscle cells undergo cellular proliferation in response to chronic cyclical mechanical strain but only in the presence of suitable concentrations of soluble growth factors. Furthermore, these growth factors do not originate from the cells in response to the mechanical strain. Therefore, the proliferation is a direct response proportional to the strain applied but dependent upon the concentration of growth factors in the overlying media. In addition the magnitude of human vascular smooth muscle cell proliferation in response to mechanical strain is dependent upon interactions between the cells and specific extracellular matrix proteins and involves activation of the mitogen-activating protein kinase intracellular signalling cascade. In conclusion, these results suggest that the narrowing of resistance vessels observed in hypertension subjects may be a direct result of the increased physical forces exerted upon the vascular smooth muscle cells in conjunction with circulating growth factors. This biological response is mediated via specific cell/matrix interactions and involves specific intracellular signalling pathways, which may provide new targets for the effective treatment and/or management of these structural alterations observed in hypertension individuals.
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Refson, Jonathan Simon. "Vein graft stenosis and the human vascular smooth muscle cell." Thesis, Imperial College London, 2000. http://hdl.handle.net/10044/1/7763.
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Beattie, David Keith. "The influence of altered haemodynamics on human smooth muscle cell behaviour." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369122.
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Sweeney, David. "Human airway smooth muscle cell Ca2+ dynamics in asthma and health." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10130.
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The funding for this research project was kindly provided by the Medical Research Council (MRC) and the British Thoracic Society (BTS)Intracellular Ca2+ homeostasis and handling were investigated in passaged human airway smooth muscle, hASM, cells from asthma and normal donors. Temporal changes in fluorescence of Ca2+-sensitive indicator fura-2 loaded into quiescent sub-confluent hASM cells were monitored using epifluorescence video microscopy. Spontaneous amplitude changes in basal fluorescence of temporal waveforms, or Ca2+ oscillations, were measured. Also, spectral analysis using the FFT transform generated a Ca2+ oscillation dominant frequency (CODF) variable. Neither amplitude nor CODF were significantly different in asthma compared to normal hASM cell donors. However, there was a significant difference (P<0.0001) between CODF in airflow obstruction (AFO), defined as FEV1/FVC<70% and FEV1< 80%, and non-AFO donors, making CODF a strong phenotypic predictor of AFO. hASM cell Ca2+ handling was investigated by Ca2+ uncaging using confocal microscopy and by bradykinin stimulation using epifluorescence microscopy. Basal Ca2+ level, Ca2+ handling exponential decay rate constants (K), SERCA activity and expression, and SOCE after a SR Ca2+-store depletion event, all demonstrated that Ca2+ handling was not significantly different between hASM cells from asthma or normal donors. There was no correlation between FEV1 and K, however there was an emerging correlation between FEV1/FVC and K for bradykinin. The postulate that Ca2+ homeostasis and handling are intrinsically dysfunctional in hASM cells from asthma compared to normal donors is ergo not supported by these data. Caffeine was found to decrease basal Ca2+ and inhibit Ca2+ oscillations in hASM cells. Future work using freshly dispersed hASM cells is required to understand in vivo Ca2+ dynamics using the methods described in this thesis. Since CODF correlates with FEV1, pattern recognition of Ca2+ oscillation frequency spectra has the potential to help define clinical asthma phenotypes. Inevitably, a post-genomic approach to comparative protein expression in asthma and normal hASM cell donors will accelerate understanding of Ca2+ dynamics.
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Comer, Brian S. "Cyclooxygenase-2 expression in asthmatic human airway smooth muscle cells." Thesis, University of South Alabama, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3608829.
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Asthmatic human airway smooth muscle cells (hASMCs) exhibit enhanced expression of numerous cytokine-responsive genes but this trend has not been observed for cyclooxygenase-2 (COX-2) expression despite knowledge that conserved regulatory mechanisms exist for cytokine-responsive gene expression. Enhanced expression of cytokine-responsive genes in asthmatic hASMCs has been attributed to differences in histone post-translational modifications and microRNA (miR or miRNA) expression. COX-2 expression is of interest because it serves as a model cytokine-responsive gene and is regulated by epigenetic mechanisms. In other cell types, miR-146a represses COX-2 and Interleukin (IL)-1β expression, directly and indirectly, respectively. Due to sequence homology, miR-146b is predicted to repress the expression of COX-2 and IL-1β. I investigated COX-2 expression in asthmatic and non-asthmatic hASMCS treated with cytomix (IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ). Also, I chose to compare histone acetylation, transcription factor binding, and miR-146a/b expression in asthmatic and non-asthmatic hASMCs to identify any correlations with COX-2 expression. A major goal of this project was to help identify new treatment targets for asthma therapeutics . I hypothesized that asthmatic hASMCs treated with cytomix express more COX-2 and secrete more prostaglandinE2 (PGE2) than non-asthmatic hASMCs due to differences in COX-2 epigenetic regulation. It is reported here that asthmatic hASMCs treated with cytomix expressed more COX-2 (mRNA/protein), and secreted more PGE2 than non-asthmatic hASMCs. Histone H3/H4 pan-acetylation at the COX-2 promoter did not increase with cytomix treatment and was not different in asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased RNA Polymerase II and nuclear factor-κB binding at the COX-2 promoter with no difference between asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased miR-146a and miR-146b expression with greater miR-146a expression in asthmatic. MiR-146a/b expression in asthmatic hASMCs treated with cytomix did not negatively correlate with COX-2 expression. These results led me to investigate whether miR-146a/b were capable of negatively regulating COX-2 and IL-1β expression in hASMCs. MiR-146a and miR-146b mimics reduced COX-2 and IL-1β mRNA/protein, and PGE2 secretion in hASMCs. MiR-146a and miR-146a/b combination inhibition increased COX-2 and pro-IL-1β protein in hASMCs but not miR-146b inhibition alone. In conclusion, elevated miR-146a expression and histone acetylation are not responsible for increased COX-2 expression in asthmatic hASMCs. MiR-146a is a minor negative regulator of COX-2 and IL-1β expression in hASMCs at physiological expression levels but mimics are capable of antagonizing cytokine-responsive gene expression profoundly. These results coupled with other evidence from the literature indicate that miR-146a/b should be investigated in animal models of asthma to determine if they are relevant asthma drug target in patients that do not respond to current anti-inflammatory therapies.
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Robins, Stephanie. "The p38 MAPK pathway in human airway smooth muscle: roles in asthma." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97233.
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The mitogen activated protein kinase (MAPK) signaling pathways play key roles in mediating inflammatory responses. Asthma is a disease characterized by excessive inflammation and the mainstay of treatment is the use of glucocorticoids which, among other effects, control the activity of p38 MAPK. Human airway smooth muscle (HASM) cells contribute to the pathology of asthma as they regulate bronchomotor tone, proliferate, migrate and secrete inflammatory cytokines. I investigated these processes in HASM using MAPK inhibitors and the glucocorticoid dexamethasone. Following TNFα stimulation, HASM cell production of GM-CSF, IL-1β, IL-33 and CXCL8 were ERK1/ERK2 dependent; all but CXCL8 were diminished by dexamethasone. Neutrophil migration in response to conditioned media from HASM cells was also ERK1/ERK2 dependent. CXCL12 displayed chemotactic activity for HASM which was shown to express the CXCR4 receptor. HASM migration was partially p38 MAPK dependent. These results highlight the potential for important and divergent roles for the MAPKs in HASM in refractory asthma.L'asthme est une maladie inflammatoire dont les glucocorticoïdes constituent le principal traitement via le contrôle de la voie p38 MAPK. Les cellules musculaires lisses bronchiques (CLM) jouent un rôle clé dans la physiopathologie de l'asthme notamment dans le remodelage des voies aériennes via leur capacité à proliférer, migrer et sécréter des médiateurs inflammatoires. La stimulation des CLM avec du TNFα entraine une activation des voies MAPK ERK et p38, induisant l'expression des gènes GM-CSF, IL-1β, IL-33 et CXCL8. L'activation de la voie MAPK ERK est importante dans la migration des neutrophiles exposée à du milieu conditionné provenant de CLM stimulées par TNFα via son rôle sur l'expression de CXCL8. En contrepartie, la voie p38 MAPK joue un rôle important dans la migration des CLM en réponse à CXCL12, un chimiokine élevée dans les bronches de patients asthmatiques. Ces résultats ont mis en évidence un rôle important et divergeant des MAPKs dans les CLM dans la pathophysiologie de l'asthme sevère.
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Sheares, Karen Kwie Kay. "The regulation of human pulmonary artery smooth muscle cell growth by hypoxia." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614833.
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Freyer, Anette M. S. "The effect of extracellular matrix on human airway smooth muscle cell phenotype." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415554.
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Corteling, Randolph Lee. "The role of TRPC channels in human airway smooth muscle cell homeostasis." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403290.
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Torrie, Lindsay J. "Characterisation of the lipopolysaccharide stimulated NF#kappa#B signal transduction pathway in rat aortic smooth muscle cell." Thesis, University of Strathclyde, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249146.
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O'Sullivan, Denis Michael. "Regulation of vascular smooth muscle cell proliferation in human coronary in-stent stenosis." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620615.
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Valente, Marie. "Characterisation of human airway smooth muscle cell lysophosphatidic acid receptors in asthma and health." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/28651.
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Lysophosphatidic acid (LPA) is a major serum phospholipid and bioactive lipid mediator that exerts a broad range of effects through its family of cognate G protein-coupled receptors via coupling to multiple G proteins and can affect a variety of cellular functions in a range of tissues and cell-types. LPA is known to affect airway function and a growing body of evidence suggests a role for LPA receptor function in the molecular aetiology of asthma. The aims of this project were to characterise the function of LPA and its receptors in cultured human airway smooth muscle (hASM) cells from asthmatic and control donors. Expression of a broad range of genes related to LPA metabolism/signalling and inflammatory signalling were analysed using both traditional and high throughput RT-qPCR methods. Decreased expression of the genes for a phosphodiesterase, PDE4B, and an LPA metabolising enzyme, LPP2, was detected in hASM cells derived from asthmatic patients compared to control donors. Investigation of LPA receptor pharmacology using a [³⁵S]GTPγS binding assay in a model cell-line showed that LPA species with a range of fatty acid tail lengths and degrees of saturation were active at LPA receptors with varying potencies. LPA exhibited complex modulation of forskolin and isoprenaline induced cAMP responses in hASM cells. Though no differences in the effects of LPA treatment were observed in the two disease-states studied, hASM cells from asthmatics exhibited a significantly higher magnitude of cAMP response compared with those from control donors, which could indicate dysfunctional adenylyl cyclase or PDE activity in disease. These findings confirm that LPA is able to affect hASM cell function in ways pertinent to asthma's pathophysiology, but do not indicate altered LPA receptor expression or function in disease.
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D'Antoni, Michelle. "The effect of decorin and biglycan on human airway smooth muscle cell proliferation, apoptosis and attachment." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103624.
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Changes in extracellular matrix (ECM) deposition along with increases in airway smooth muscle (ASM) mass are characteristic features of airway remodeling which contribute to asthma pathophysiology. Modifications in ECM include increased collagen deposition and altered proteoglycans (PGs) levels. While biglycan, a small leucine-rich PG (SLRP), deposition is generally increased, changes in decorin, another SLRP, are more variable. The interaction between the cell and the surrounding ECM triggers numerous cellular responses, which modulate functions such as survival, proliferation and differentiation. Since decorin and biglycan are known to influence cell behaviour in various types of cells, we hypothesized that these molecules would affect human airway smooth muscle cell (HASMC) function. We sought to determine the effects of decorin and biglycan on HASMC proliferation, apoptosis and attachment, and to explore the putative mechanisms responsible for these effects. Collagen type I was used as a control.Culture on a decorin matrix caused a decrease in HASMC number, which was attributed to a decrease in proliferation and an increase in apoptosis. Culture on biglycan caused an initial decrease in cell number that was not sustained. Collagen caused a significant increase in cell number. Neither biglycan nor collagen caused changes in proliferation or apoptosis. Subsequent experiments showed that cell anchorage to decorin and biglycan matrices caused abnormal focal adhesion and cytoskeletal organization, as well as, increases in alpha2 integrin protein levels as compared to cells seeded on collagen or plastic. To assess integrin activation, focal adhesion kinase (FAK) protein levels and activation were measured. FAK levels were significantly decreased compared to cells cultured on plastic or collagen I, but activation levels were unchanged.These studies demonstrate that PGs have differential effects on HASMC growth. Whereas decorin reduces ASM proliferation and increases apoptosis, biglycan has no effect. Cell-matrix adhesions were irregular in HASMCs seeded on decorin or biglycan compared to cells on collagen I or plastic. Decreases in decorin in the asthmatic airway wall, as observed in fatal asthma cases, may permit more exuberant ASM hyperplasia, suggesting that decorin's presence could serve a protective role by modulating the increase in ASM mass in asthma.Les changements de composition de la matrice extracellulaire (MEC) ainsi que l'augmentation de la masse du muscle lisse des voies aériennes sont des caractéristiques du remodelage des voies aériennes qui contribuent à la physiopathologie de l'asthme. Les modifications de la MEC comprennent une augmentation du dépôt de collagène et un changement du niveau des protéoglycanes (PGs). Le dépôt de biglycane, un petit PG riche en leucine, est généralement plus élevé. Les changements d'expression de la décorine, un autre petit PG riche en leucine, sont, par contre, plus variables. L'interaction entre la cellule et la MEC qui l'entoure, déclenche de nombreuses réponses cellulaires, telles que la survie, la prolifération et la différenciation. Étant donné que la décorine et le biglycane peuvent influencer le comportement de différents types de cellules, nous avons émis l'hypothèse que ces molécules auraient aussi un effet sur la fonction des cellules musculaires lisses des voies aériennes. Nous avons cherché à déterminer les effets de la décorine et du biglycane sur la prolifération, l'apoptose et l'attachement des cellules musculaires lisses des voies aériennes. Nous avons aussi exploré les mécanismes putatifs qui seraient responsables de ces effets en utilisant le collagène de type I sera comme traitement de référence. La culture des cellules sur une matrice de décorine a provoqué une diminution du nombre cellules musculaires lisses des voies aériennes due à une diminution de la prolifération et à une augmentation de l'apoptose. La culture sur le biglycane a causé initialement une diminution du nombre de cellules, mais cette baise n'a pas été maintenue. Le collagène a provoqué une augmentation significative du nombre de cellules. Ni le biglycane ni le collagène n'ont induit des changements au niveau de la prolifération ou de l'apoptose. Des expériences ultérieures ont démontré que l'ancrage des cellules musculaires lisses des voies aériennes sur des matrices de décorine et de biglycane était anormal, ainsi que la formation d'adhésions focales et l'organisation du cytosquelette, en comparaison avec les cellules ensemencées sur du collagène ou du plastique. De plus, l'augmentation d'expression protéique de la sous-unité alpha2 d'intégrine a également été observée. Pour évaluer l'activation des intégrines, le niveau de protéine, ainsi que l'activation de la kinase des adhésions focales (FAK) ont été mesurés. En présence de décorine, l'expression protéique de FAK était significativement diminuée comparativement aux niveaux produits par les cellules ensemencées sur du plastique ou du collagène bien que le niveau d'activation était inchangé. Ces études démontrent que les PGs ont des effets distincts sur la croissance des cellules musculaires lisses des voies aériennes: la décorine a réduit la prolifération et a augmenté l'apoptose des cellules, tandis que le biglycane n'a pas modifié ces paramètres. Les adhésions cellules-matrice des cellules musculaires lisses des voies aériennes ensemencées sur la décorine ou le biglycane étaient irrégulières par rapport aux cellules sur le collagène de type I ou le plastique. La diminution de la quantité de décorine dans la paroi des voies aériennes observée dans les cas d'asthme fatal pourrait entraîner une hyperplasie plus prononcée des cellules musculaires lisses des voies aériennes. Ceci suggère que la présence de la décorine pourrait jouer un rôle protectif dans l'asthme, en modulant l'augmentation de la masse du muscle lisse des voies aériennes.
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Yoo, Edwin. "Inflammatory cytokines induce human bronchial smooth muscle cell proliferation via an NCX-1 dependent mechanism." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/fullcit?p1477952.
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Thesis (M.S.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed July 16, 2010). Available via ProQuest Digital Dissertations. Includes bibliographical references (leaves 36-40).
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Awad, Suad Salih. "Characterization and modulation of the ryanodine-sensitive calcium release mechanisms in human smooth muscle cell." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363527.
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Lee, Elaine. "Effects of cytokines and monocytes on matrix metalloproteinases in human vascular smooth muscle cell cultures." Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/36651.
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Davis, Elaine C. (Elaine Caroline). "Interrelationships of endothelial and smooth muscle cells to elastic laminae in the mouse aortic wall during development : an ultrastructural, immunohistochemical and radioautographic study." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=39360.
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The association of endothelial and smooth muscle cells to elastic laminae in the developing mouse aortic wall was investigated by electron microscopy and immunohistochemistry. Early in development, bundles of contractile filaments traverse the long axis of the cell obliquely to anchor in membrane-associated dense plaques on either side. From these sites, microfibrils extend in the same direction to link the cell to the adjacent elastic laminae. The microfibrils become infiltrated with elastin to form elastin extensions, which together with the intracellular contractile filaments bundles, forms a "contractile-elastic unit". The ordered arrangement of contractile-elastic units revealed in the adult vessel provides a mechanism for the transmission of tension throughout the vessel wall. During development, endothelial cells are similarly connected to the subjacent elastic lamina by filamentous structures. These "endothelial cell connecting filaments" show morphological feature similar to microfibrils. Immunolocalization of fibrillin, a constituent protein of microfibrils, to the connecting filaments provides further evidence for their microfibrillar nature. These results suggest that microfibrils may play an important role in cell anchorage and the maintenance of tissue integrity. A longterm radioautographic study was performed to provide quantitative data concerning the stability of aortic elastin. Results from this study demonstrate the remarkable longevity of elastin in the aortic wall and suggest that, like elastin, cell to elastic lamina connections remain stable throughout development and exist as functional structures in the adult vessel.
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Pravda, Zuzana. "Identification of differentially expressed genes during differentiation of a novel human vascular smooth muscle cell line." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0002/MQ42194.pdf.
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Hollins, Fay Marie. "Human airway smooth muscle promotion of mast cell survival and proliferation, and altered state of activation in asthma." Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/4794.
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Asthma is a condition that is characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), chronic airway inflammation and airway remodeling. There is microlocalisation of mast cells within the airway smooth muscle (ASM) bundle in asthma at a level significantly above health and other respiratory diseases. These cells are recruited and their survival promoted. However, their functional consequences have yet to be discovered. AHR in asthma is a result of increased responsiveness of the ASM to agonist and has found to increase with localized mast cell numbers. This phenomenon could be a result of an intrinsic abnormality or of local effects. So far, it has yet to be elucidated. We sort to examine this phenomenon of the presence of mast cells within the ASM and the increased responsiveness of the ASM; mechanisms involved in sustaining mast cell numbers, and the intrinsic differences of ASM between asthma and health. ASM had the ability to maintain survival and promote proliferation of co-cultured mast cells, a mechanism supported by the actions of stem cell factor (SCF), interleukin (IL)-6 and cell adhesion molecule (CADM)-1. There was a physical interaction in mast cell adhesion to ASM between CADM1 and the SCF receptor. The co-culture also enhanced constitutive mast cell degranulation. Intracellular calcium levels of ASM from asthmatic patients at rest were found to oscillate to a great degree. Following stimulation with agonist, the ASM gave a reduced intracellular calcium response. However, their contractile ability measured still remained greater than ASM isolated from non-asthmatic subjects. SCF, IL-6 and CADM1 supported the survival of mast cells co-cultured with ASM. Although ASM from asthmatic subjects produce a reduced intracellular calcium response to agonist, at baseline these cells are more activated and they still retain their increased contractile response. Mechanisms which may contribute to the altered airway physiology in asthma.
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Alshanwani, Aliah Rajib M. "Role of microRNA-21 in the regulation of human saphenous vein smooth muscle cell function and vascular remodelling." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/15329/.
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Cardiovascular diseases including coronary artery disease are the major cause of death worldwide. Saphenous vein (SV) bypass grafting is widely used to revascularise atherosclerotic coronary arteries, although failure rates are problematic. Adverse remodelling and intimal hyperplasia (IH) underlie graft failure primarily driven by aberrant smooth muscle cell (SMC) function. Whilst altered SMC function is pivotal to the adaptation of SV grafts, in the longer term excessive cell proliferation and migration lead to intimal hyperplasia that compromises patency rates. Whilst there are no pharmacological agents to effectively prevent IH, accumulating evidence has implicated microRNAs (miRs), short non-coding RNAs that negatively regulate gene expression, in SMC phenotypic changes and vascular remodelling. In particular, miR-21 is highly expressed in the cardiovascular system and is reportedly dysregulated in pathological conditions. This thesis confirmed a distinct phenotype in SV-SMC from T2DM patients, relative to those from patients without diabetes (ND), although this was not associated with differential miR-21 expression. Artificial overexpression of miR-21 in ND SV-SMC increased total cell area and cell proliferation and its knockdown was able to reverse the increase in cell area. In addition, treating SV-SMC with PDGF-BB, commonly associated with vascular remodelling, led to increased miR-21 expression through activation of both ERK and Akt; inhibition of either pathway abrogated miR-21 expression. Exploring the downstream target genes of miR-21 using a vascular remodelling specific array and follow-up RT-PCR yielded two genes affected by miR-21 overexpression; increased MMP-1 mRNA and decreased IL-1A mRNA. Surprisingly, SV-SMC migration in cells overexpressing miR-21 did not, however, modulate migration through collagen-1 or -3 coated membranes. Potential downstream target genes of miR-21 mediating functional changes related to SMC proliferation and migration were tested. Whilst there were no clear effects on “classical” targets (PDCD4, PTEN and Spry), a significant downregulation of RECK mRNA and protein in miR-21 overexpressing SV-SMC was apparent. Further studies are required to explore in detail how RECK is involved in miR-21 mediated cellular functions and whether targeting miR-21 in SV-SMC would provide a promising therapeutic strategy to improve outcomes in patients following SV grafting.
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Nakao, Tetsushi. "Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-inflammatory Pathways." Kyoto University, 2018. http://hdl.handle.net/2433/231004.
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Unlu, Sebnem. "Role of isoprenylation in the control of cell proliferation and apoptosis in human vascular smooth muscle cells in culture." Thesis, Imperial College London, 2000. http://hdl.handle.net/10044/1/8577.
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Pang, Linhua. "The induction of cyclooxygenase-2 in cultured human airway smooth muscle cells and its role in regulating the cell functions." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301656.
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Alharthi, Sameer E. M. "The effect of mitogen-activated protein kinase phosphatase-2 (MKP-2) over-expression via infection with Adv.MKP-2 on human endothelial cell apoptosis and vascular smooth muscle cell proliferation." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14479.
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Cuneo, Anthony. "THERAPEUTIC MECHANISMS OF INTERLEUKIN-19 FOR VASCULAR PROLIFERATIVE DISEASES." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/78032.
Full textAbstract:
Molecular and Cellular PhysiologyPh.D.
Cardiovascular disease is the leading cause of mortality in the western world. The pro-inflammatory and pro-proliferative etiology of vascular proliferative diseases is well characterized, while much less is known about the mechanisms of anti-inflammatory and anti-proliferative processes. Interleukin-19 (IL-19) is a newly described member of the IL-10 family of anti-inflammatory interleukins, and our group was the first to discover IL-19 expression in activated, synthetic, but not quiescent, contractile human vascular smooth muscle cells (hVSMC). We also found that IL-19 is anti-inflammatory and anti-proliferative for hVSMC. IL-19 is able to reduce the abundance of COX-2, IL-1β, IL-8, and Cyclin D1 transcripts which contain AU-rich elements (ARE) in their 3'-untranslated regions (3'-UTR). IL-19 is able to reduce the abundance of HuR, a stabilizing RNA-binding protein, which we feel provides a mechanism for these effects. The overall goal of this study is to elucidate IL-19's anti-inflammatory and anti-proliferative mechanism(s) in hVSMC in the context of vascular proliferative diseases. This goal has directed our overall hypothesis: IL-19's anti-proliferative and anti-inflammatory effects in hVSMC are mediated, at least in part, by modulation of HuR abundance and translocation, resulting in decreased stability of mRNA transcripts. HuR functions through a translocation mechanism, and IL-19 is able to reduce HuR cytoplasmic abundance. IL-19 also reduces HuR phosphorylation, which is a pre-requisite for HuR translocation, possibly through a PKCα-dependent mechanism. The stability of ARE-containing transcripts is reduced with IL-19 treatment, and reducing HuR expression by siRNA has the same inhibitory effect. VSMC are important mediators in the initiation of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) is able to induce IL-19 expression in these cells. VSMC are known to express scavenger receptors that take up ox-LDL. IL-19 is able to reduce the uptake of ox-LDL and the abundance of ox-LDL induced LOX-1 and CX-CL16 scavenger receptors. Interestingly, these scavenger receptors also have ARE in their 3'-UTR. IL-19 is able to reduce ox-LDL induced HuR cytoplasmic abundance. HuR knockdown by siRNA reduces the uptake of ox-LDL by hVSMC. These data suggest that IL-19 reduced scavenger receptor abundance may be due to decreased total and cytoplasmic HuR abundance. IL-19 reduces the abundance of ox-LDL induced COX-2 expression. Taken together, these results demonstrate that IL-19 down-regulates vital steps in vascular proliferative disease processes through an HuR-dependent mechanism.
Temple University--Theses
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Martinez, Elizabeth Ferreira. "Estudo da expressão da a-actina de músculo liso em cultura de células de polpas dentárias e gengivas humanas tratadas com o fator de transformação de crescimento b1(TGF-b1)." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-09092008-115547/.
Full textAbstract:
Durante o processo de reparação tecidual, o fator de transformação de crescimento b1 (TGF-b1) apresenta um importante papel na regulação da expressão da a-actina de músculo liso (a-AML) e portanto, na diferenciação miofibroblástica. Como os fibroblastos pulpares apresentam características peculiares, com a expressão de proteínas específicas que os diferem de fibroblastos de outros tecidos conjuntivos, o presente estudo avaliou in vitro se o TGF-b1 aumenta a expressão de a-AML em fibroblastos pulpares humanos comparando-os com fibroblastos de gengiva. Para tal, diferentes doses de TGF-b1 (5 à 10 ng/ml) foram adicionadas às culturas de células, sendo a expressão da a-AML analisada por imunofluorescência e western-blotting. Ambos os tipos celulares imunoexpressaram a-AML mesmo sem o tratamento com o TGF-b1, estando aumentada consideravelmente, quando o TGF-b1 foi adicionado às culturas. Os resultados do presente estudo demonstraram que o TGF-b1 induz a expressão de a-AML, sugerindo a indução do fenótipo miofibroblástico em fibroblastos pulpares.Transforming growth factor-beta 1 (TGF-b1) has been related to induce the expression of a-smooth muscle actin (a-SMA) in fibroblasts during repair. Since pulpal fibroblasts seem to be somewhat different from other fibroblasts, the present study investigated in vitro whether TGF-b1 enhances the expression of a-SMA in human pulpal fibroblasts. TGF-b1 was added in doses between 5-10 ng/ml to cultures of both dental pulp and gingiva human fibroblasts. The expression of a-SMA was analyzed by immunofluorescence and western-blotting. Both cell types were immunoreactive for a-SMA even without TGF-b1. When TGF-b1 was added to cell cultures, the expression of a-SMA increased dramatically in pulpal fibroblasts, independent of the concentration used. It was confirmed by the western blot analysis. The present findings showed that TGF-b1 up-regulated the expression of a-SMA thus inducing pulpal fibroblasts to acquire the myofibroblast phenotype.
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Riches-Suman, Kirsten, E. Clark, R. J. Helliwell, T. G. Angelini, K. E. Hemmings, M. A. Bailey, K. I. Bridge, D. J. A. Scott, and K. E. Porter. "Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease." 2017. http://hdl.handle.net/10454/14364.
Full textAbstract:
YesAbdominal aortic aneurysm (AAA) is a silent, progressive disease with high mortality and increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (5cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of differentiation marker miR-145 (2.2-fold, P<.001) and senescence marker SIRT-1 (1.3-fold, P<.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, P<.001 and 1.8-fold, P<.01 respectively, versus control cells) and displayed aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker H2AX (3.9-fold, P<.01 vs. control SMC). These features did not correlate with patients’ chronological age; and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at end-stage disease. Refinement of a porcine bioreactor model would facilitate study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression.
Supported in part by a grant from the Leeds Teaching Hospitals Charitable Foundation (9R11/8002)
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Specht, Danyel. "Targeted drug delivery to human aortic smooth muscle cells using biodegradable nanoparticles." 2008. http://hdl.handle.net/10106/1106.
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Shi, Junyan Jr. "Insulin Promotes Elastin Production in Cultures of Human Aortic Smooth Muscle Cells and Skin Fibroblasts." Thesis, 2011. http://hdl.handle.net/1807/32923.
Full textAbstract:
Elastic fibers are major components of ECM, providing tissues with resilience and elastic recoil. They consist of the insoluble elastin made of cross-linked precursor tropoelastin monomers and the microfibrillar scaffold.
Various connective tissue disorders have been linked to elastic fiber malformation. In addition, it has been shown that decreased vascular elastin contents correlate with the rapid progression of atherosclerosis in patients with diabetes mellitus. However, it is unknown whether insulin can directly modulate elastogenesis. This question was addressed in this thesis.
Our study revealed that insulin stimulated elastogenesis in cultures of human aortic SMCs and skin fibroblasts, and that this effect of insulin was transduced through the insulin receptor. We found that insulin might initiate elastin gene expression and enhance tropoelastin secretion. We also presented novel preliminary data indicating that Glut10 might bind to a fraction of intracellular tropoelastin, and that insulin might modulate the association between these two proteins.
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Huang, Chung-wei, and 黃政韋. "Effect of Superoxide on the Angiotensin II-elicitedCalcium Response in Human Aortic Smooth Muscle Cells." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/7575g9.
Full textAbstract:
碩士國立中正大學
化學工程所
93
Angiotensin II (Ang II) is one of the atherosclerotic risk factors, which increases cytosolic calcium concentration via inositol 1,4,5-trisphosphate (IP3) signal pathway in vascular smooth muscle cells (SMCs), resulting in cell contraction. In addition, Ang II can also raise the level of intracellular superoxide anion (O2-) via NAD(P)H oxidase. Nitric oxide (NO) has been shown to inhibit mobilization of IP3-gated calcium channel through increased intracellular cyclic guanine monophosphate (cGMP). Furthermore, we have previously demonstrated that superoxide determines the SMC-NO uptake rate. Therefore, it is likely that Ang II may use O2- to increase the SMC-NO uptake rate, which may in turn serve as a negative feedback circuitry of calcium response. To demonstrate the role of superoxide in the Ang II-elicited calcium response, first we demonstrated that the calcium response is in an Ang II dependent manner using fluorescent dye, Fura-2, with a fluorescence spectrophotometer. After verifying the assay for calcium response, we had SMCs compete with oxyhemoglobin for NO during the Ang II challenge. Pretreatment of SMCs with NADPH or SOD inhibitors decreases the Ang II-elicited calcium response. In contrary, pretreatment of tiron, a superoxide scavenger, increases the Ang II-elicited calcium response. Taken together, our results demonstrate that superoxide in smooth muscle cells modulates negatively the Ang II-elicited calcium response via increasing the SMC-NO uptake, suggesting the beneficial role of superoxide in SMCs in the blood vessel response.
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Papadaki, Maria. "Effect of fluid shear stress on the growth and metabolism of human aortic smooth muscle cells." Thesis, 1997. http://hdl.handle.net/1911/19194.
Full textAbstract:
Upon disruption of the integrity of the endothelial monolayer, smooth muscle cells (SMC) may be directly exposed to blood flow and their behavior may be modulated by the local hemodynamic environment. Furthermore, modeling studies indicate that in the normal vasculature, underlying SMC are exposed to significant shear stresses due to transmural interstitial flaw. To study the contribution of fluid shear stress to SMC growth and metabolism, cultured human aortic smooth muscle cells (hASMC) were subjected to physiological levels of shear stress using parallel plate flow chambers connected to recirculating flow loops.
Fluid shear stress decreased the growth rate of hASMC. The cell number at high shear stress levels was significantly lower compared to low levels of shear stress and this was not a result of cell injury. These findings are consistent with in vivo observations in which it was found that areas of low shear stress were associated with greater intimal hyperplasia. Exposure of SMC to shear stress resulted in a rapid nitric oxide (NO) release which was followed by a sustained nitrite production, independent of the level of shear stress in the range of 5-25 dyn/cm$\sp2$. NO production was calcium dependent and was due to activation of a constitutive nitric oxide synthase (NOS) I. The constitutive expression of NOS in SMC and its concomitant activation by shear stress may play a regulatory role in the blood vessel wall in the absence of endothelium following vascular injury, and may also be important in normal vessel homeostasis.
Shear stress differentially mediated the expression of thrombin receptor (TR) and tissue plasminogen activator (tPA) in hASMC. The upregulation of tPA and downregulation of TR mRNA and protein by high shear stress are consistent with the relative paucity of lesions in areas of high shear stress within the vasculature, while the downregulation of tPA and upregulation of TR mRNA by low shear stresses are consistent with the known predilection of low shear stress areas to thrombus formation and to vascular cell proliferation. The finding of a domain within the TR promoter that contains a potential shear responsive element offers new insights into these regulatory events.
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Chen, Ying-Hui, and 陳應輝. "ROS production and the NADPH oxidase expression in human abdominal aortic aneurysm-derived smooth muscle cells." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/50897172642248514288.
Full textAbstract:
碩士國立成功大學
細胞生物及解剖學研究所
93
Abdominal aortic aneurysms (AAAs) are present in 3-8% of people over 60 years of age in America. It usually occurs below the renal arteries and may extend into the iliac arteries. Progression of AAA involves dilation, stretching, or ballooning of the aorta. The causes of AAA may include infection, congenital weakening of the connective tissue component of the artery wall, or trauma. This is often a silent disorder until the catastrophic event of aneurysm rupture occurs. Most AAAs occurs in association with advanced atherosclerosis and hypertension. In the past decade, reactive oxygen species (ROS) have been proposed to contribute to the pathogenesis of aneurysm though the exact cause is still unknown. ROS is often considered cytotoxic metabolites during oxidative process from oxygen to water. NAD(P)H oxidase has been reported as a major enzyme for producing ROS in most of the vascular inflammatory diseases. Miller et al showed that tissue of aneurysm produced more ROS then adjacent area. In this study, we hypothesized that AAA-derived human aortic smooth muscle cells (HASMCs) are capable of more ROS production accompanied by higher NAD(P)H oxidase activity. Six AAA specimens were collected from surgery under normal surgical procedure. Specimens from the punctured hole of ascending aorta in patients with coronary artery bypass graft surgery were collected as the controls. HASMCs were cultured from medial layer of the specimens by explant method and the identity of HASMCs was verified by immunostaining with specific markers. AAA-derived and control HASMCs exhibited similar morphological and immunostaining features in culture. The proliferation rate determined by MTT assay showed no difference between the two groups. Angiotensin II-stimulated superoxide anion production as detected by dihydroethidium-derived fluorescence was markedly greater in AAA-derived HASMCs compared to the control HASMCs while no difference was detected in the absence of stimulation. Similarly, angiotensin II stimulation resulted in 2-fold in NAD(P)H oxidase activity assay in AAA-derived HASMCs compared to control HASMCs with similar basal activity in both groups. The above experiments may characterize the important roles of ROS and NAD(P)H oxidase in mediating the disease of AAA.
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Niibori, Yoshiko. "Regulation of inositol phospholipid hydrolysis by extended treatment with angiotensin II in human aortic smooth muscle cells." Thesis, 2003. http://hdl.handle.net/1957/30353.
Full textAbstract:
Long-term stimuli of many systems leads to decreased cellular
responsiveness, or desensitization. We characterized the desensitization of
angiotensin II (Ang 11)-mediated inositol phospholipid (IP) hydrolysis in cultured
human aortic smooth muscle cells (HASMC). Although it has been suggested that
the desensitization induced by long-term Mg II exposure may result partially from
down-regulation of Ang II receptor, this is not sufficient to explain fully
desensitization in many systems. Post-receptor desensitization of IP hydrolysis
may also result from phosphorylation or changes in protein levels of the effector
enzyme, PLC-β. We identified the major PLC-β isoenzymes expressed by
HASMC as PLC-β1 and PLC-β3. Ang II pretreatment reduced IP accumulation
induced by Ang II (1μM) in a time-dependent manner. Phorbol ester-12-myristrate-13-acetate (PMA), a protein kinase C (PKC) activator, also reduced
Ang II-stimulated IP accumulation. These results suggest that PKC activation may
negatively regulate Ang II-stimulated IP signaling in HASMC, similar to rat cells.
In addition, PKC also reduced IP accumulation stimulated by A1F₄⁻, directly
activating the G protein. It suggests that the majority of PKC-induced
desensitization of Ang II-stimulated IP signaling occurs downstream of the Ang II
receptor in HASMC. However, both PLC-β1 and PLC-β3, expected candidates for
PKC phosphorylation, were phosphorylated independently of PKC activation or
inhibition, indicating that PKC might not be involved in direct phosphorylation of
PLC-β1 and PLC-β3. Furthermore, PLC-β1, but not PLC-β3, was highly
phosphorylated under basal conditions, suggesting that PLC-β1 and PLC-β3 may
play different roles in IP signaling in HASMC.Graduation date: 2003
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Wei, Tzu-Kui, and 魏子貴. "Negtive Feedback Regulation of Superoxide on Angiotensin II-Induced Calcium Response in Human Aortic Smooth Muscle Cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/65315361261340796315.
Full textAbstract:
碩士國立中正大學
化學工程所
95
Angiotensin II (Ang II), a multifunctional hormone, increases cytosolic calcium concentration via inositol 1,4,5-trisphosphate (IP3) signaling pathway in vascular smooth muscle cells (VSMCs), resulting in cell contraction. In addition, Ang II can also raise the level of intracellular superoxide (O2-) via activation of NAD(P)H oxidase. Nitric oxide (NO), on the other hand, has been shown to inhibit mobilization of IP3-gated calcium channel through increased intracellular cGMP. We have previously demonstrated that O2- determines NO uptake rate by VSMCs. Thus, it is likely that Ang II may increase the VSMC-NO uptake rate though production of O2-, which may in turn serve as a negative feedback circuitry for the AngII-induced calcium response. To demonstrate the role of O2- in the Ang II-induced calcium response, first we showed that the calcium response is in an Ang II dependent manner using fluorescent dye, Flou-4, with a fluorescence microscope. Furthermore, we had VSMCs compete with oxyhemoglobin for NO during the Ang II challenge. Our results showed that pretreatment of 5 mM Tiron (an O2- scavenger) increased the Ang II-induced calcium response. On the other hand, the Ang II-induced calcium response was reduced by pre-incubation of VSMCs with a lower concentration of NADPH (0.1 mM) but was elevated with a higher concentration of NADPH (10 mM), suggesting the differential effect of O2- on the Ang II-induced calcium response. Pretreatment with 4 μM Ebselen abolished Ang II-induced calcium response due to inhibition of a number of enzymes such as protein kinase C, NADPH oxidase, and IP3-induced calcium release except peroxynitrite scavenge. Taken together, our results demonstrate that moderate levels of O2- in VSMCs modulates negatively the Ang II-induced calcium response via increasing the VSMC-NO uptake rate, suggesting a beneficial role of O2- in VSMCs in the blood vessel response.
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Chu, Ting-Hui, and 朱庭慧. "The effects of SOD and catalase overexpression on the proliferation of oxLDL-treated human aortic smooth muscle cells." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/97923342910194468220.
Full textAbstract:
碩士國立陽明大學
解剖暨細胞生物學研究所
91
The migration of smooth muscle cells (SMCs) into the intima, followed by their proliferation is a central theme of atherosclerosis and restenosis. Many lines suggest that the effects of antioxidant enzymes on the proliferation of SMCs play a key role in the prevention and treatment of cardiovascular disorders. The present study was designed to examine the ability of catalase and Cu/Zn superoxide dismutase (Cu/Zn SOD) expression modulating the proliferation and the production of reactive oxygen species (ROS), Human aortic smooth muscle cells (HASMCs) were infected with adenoviral vectors containing cDNA of human catalase (AdCAT) or Cu/Zn SOD (AdSOD). The infection with AdCAT or with AdSOD protein greatly increased the amount of functional catalase and SOD protein contents within HASMCs cytoplasm by Immunocytochemical staining, Western blot, and Enzyme activity assay. We examined cell survival rate by using MTT assay, cellular hydrogen peroxide and superoxide production by DCFH-DA and DHE, cellular MAPK signal pathway by Western blot, the activation of transcription factors by EMSA, and the cell proliferation by BrdU incorporation assay. HASMCs treated with 20 mg/ml oxidized low-density lipoprotein (oxLDL) for 24 hours induced cell proliferation, stimulated hydrogen peroxide and superoxide anion production, activation of MAPK (ERK1/2, p38, JNK1/2) signal pathway as well as transcription factors (AP-1 and NF-kB). Transfection with 50 MOI AdSOD, AdCAT or AdCO in 20 mg/ml oxLDL-treated HASMCs could separately reduce cellular superoxide anion and/or hydrogen peroxide production. Besides, transfection with the three kinds of cDNA could inhibit oxLDL-activated ERK1/2 and JNK 1/2 MAPK signal pathway, AP-1 and NF-kB expression and cell proliferation. HASMCs treated with MAPK inhibitors (PD98059, SB203580 or SP600125) would effectively inhibit oxLDL-activated MAPKs (ERK1/2, p38, JNK1/2) signal pathway, transcription factors of AP-1 and NF-kB expression and cell proliferation. These results suggest that antioxidant enzymes may play protective roles in the pathogenesis of atherosclerosis and restenosis by reducing ROS production and inhibiting SMC proliferation.
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Lin, Hsing-Chun, and 林杏純. "Curcumin and Carnosic acid inhibit MMP-9 activity and migration of cytokine-induced human aortic smooth muscle cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/97935505708937289761.
Full textAbstract:
碩士中國醫藥大學
營養學系碩士班
95
In the United States and other Western countries, atherosclerosis is the leading cause of illness and death. The migration and matrix metalloproteinases (MMPs) activation of vascular smooth muscle cells (VSMCs) may play key roles in the development of atherosclerosis. Curcumin, which is consumed daily by millions of people, is a polyphenol derived from the plant Curcuma longa. In general, curcumin has been associated with a large number of biological and cellular activities, including antioxidative, anti-inflammatory, anticarcinogenic, and hypocholesterolemic properties. Carnosic acid (CA) is the primary phenolic compound in rosemary and salvia. Previous study indicated that CA possesses antioxidant activity in vitro. In this study, we investigated the inhibitory effect of curcumin and CA on tumor necrosis factor-α (TNF-α)-induced the migration in human aortic smooth muscle cells (HASMCs) and MMP-9 activity. The migration assay showed that curcumin and CA effectively inhibited the TNF-α-induced migration of HASMCs as compared with the control group. Curcumin and CA lowered the secretion and protein expression of MMP-9 by gelatin zymography and western blot assays. They also decreased nuclear translocation of nuclear factor-κB (NF-κB) p50, p65, and ROS production. In conclusion, curcumin and CA inhibit TNF-α-induced nuclear translocation of p50 and p65, thereby suppressing the secretion and protein expression of MMP-9, resulting in decreased HASMCs migration. Thus, curcumin and CA have anti-inflammatory properties and may play important roles in the prevention of atherosclerosis.
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Chen, Hsin-chieh, and 陳信杰. "Detection of the intracellular superoxide concentration in human aortic smooth muscle cells upon angiotensin II challenge using fluorescence microscopy." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/93600277139981310723.
Full textAbstract:
碩士國立中正大學
化學工程所
96
Angiotensin II (Ang II), a risk factor for atherosclerosis, increases cytosolic calcium concentration by generating inositol 1,4,5-trisphosphate (IP3) via activation of phospholipase C (PLC) in smooth muscle cells (VSMCs), resulting in cell contraction. Ang II can also produce superoxide (O2-) via activation of NADPH oxidase. The change of intracellular O2- is usually measured using flow cytometer (FACS). In this study, a fluorescence microscope with a fluorescent dye, hydroethidine (HE), was used to monitor the induction of intracellular O2- by Ang II. The result shows that Ang II increases the intracellular O2- in a dose dependent manner. Addition of the NO donor increases the HE-mediated fluorescence, indicating a higher fluorescence yield for the reaction product of peroxynitrite (OONO-) and HE as compared to that of O2- and HE. Furthermore, the generation of O2- by Ang II is enhanced in the presence of oxyhemoglobin (Hb), which can be inhibited by NO or Tiron. Pretreatment of NADPH augments the Ang II-induced fluorescence of HE due to the increase of O2- production. In addition, 4 µM ebselen is able to abolish peroxynitrite-mediated fluorescence of HE. In conclusion, our results demonstrate the fluorescence microscopy is a useful alternative method on monitoring the alteration of intracellular O2- and OONO-.
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Shih, Meng-Chun, and 施孟均. "The effect of antioxidant enzymes on the proliferation of oxLDL-treated human aortic smooth muscle cells and its underlying mechanism." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/33959431110805111947.
Full textAbstract:
碩士國立陽明大學
解剖暨細胞生物學研究所
92
The migration of smooth muscle cells (SMCs) into the intima, followed by their proliferation is a central theme of atherosclerosis and restenosis. These events are preceded and accompanied by oxidized low-density lipoprotein (oxLDL). Many lines suggest that possible effects of antioxidants on the inhibition of LDL oxidation and smooth muscle cell proliferation could play a key role in the prevention and treatment of cardiovascular disorders. The present study was designed to examine the effect and the mechanism of overexpression of antioxidant enzymes, catalase and Cu/Zn superoxide dismutase (SOD), on the proliferation of oxLDL-treated human aortic smooth muscle cells (HASMCs). HASMCs were infected with adenoviral vectors containing cDNA of human catalase (AdCAT)、 Cu/Zn SOD (AdSOD) or catalase and Cu/Zn SOD (AdCO). The infection with AdCAT or with AdSOD protein greatly increased the amount of catalase or SOD protein contents within HASMCs cytoplasm by Western blot. We examined cell survival rate by using MTT assay, activity of NADPH oxidase by NADPH oxidase activity assay, cell cycle status by flow cytometry, and expression of cell cycle related proteins、and cellular Akt by Western blot. HASMCs treated with 20 □g/ml oxLDL for 24 hours induced increase of cell viability, activation of NADPH oxidase, stimulation of G1→S cell cycle progression, activation of Akt signal pathway, and the increase of the expressing of the cell cycle inducers (cyclin D1、cyclin E、CDK2、CDK4 and pRb ). Transfection with 50 MOI AdCAT, AdSOD or AdCO in 20 □g/ml oxLDL-treated HASMCs could reduce the activation of NADPH oxidase. Besides, transfection with the three kinds of cDNA could inhibit oxLDL-activated Akt signal pathway, decrease cyclin D1、cyclin E、CDK2、CDK4 and pRb, enhace the CDK inhibitors, p21、p27, and arrest cell cycle in the G0/G1 phase in oxLDL-stimulated HASMCs. These results suggest that antioxidant enzymes may play protective roles in the pathogenesis of atherosclerosis and restenosis by reducing ROS production and inhibiting SMC proliferation.
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Hu, Cing-Siang, and 胡青香. "The effect of Salvianolic acid B on ICAM-1 and Cox-1 expression of lipopolysaccharide-treated human aortic smooth muscle cells." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/76350708620381305670.
Full textAbstract:
碩士國立陽明大學
解剖暨細胞生物學研究所
92
Abstract Atherosclerosis is considered as an inflammatory disease because adhesion of leukocytes and expression of adhesion molecules are present in atherosclerotic lesions. Inaddition reactive oxygen species (ROS) contriute to the pathogenesis of atherosclerosis. The NAD(P)H oxidase is a predominant source of ROS. Previous studies have show that lipopolysaccharide (LPS), an endotoxin, is a potent activator in the immune system. It is also known that NO production and COX-2 expression were strongly induced by LPS. Salvia miltiorrhiza (SM) is an herb which is widely used in the treatment of cardiovascular disorders. Salvianolic acid B (Sal.B), purified from Salvia miltiorrhiza (SM), is a strong water-soluble phenolic antioxidant. In present study, human aortic smooth muscle cells (HASMCs) treated with 0.1 □g/ml LPS were found to increase proliferation, NAD(P)H oxidase activity, PGE2 production, expression of ICAM-1, IL-1□, p47 phox, COX-2 and COX-2mRNA . LPS treatment also increased the phosphorylation of ERK1/2 and JNK. Pretreatment of HASMCs with Sal. B (10 □M, 24 hours) attenuated LPS-induced the NAD(P)H oxidase activity, PGE2 production, expression of ICAM-1, IL-1□, p47 phox, COX-2 and COX-2 mRNA. Sal. B also decreased the phosphorylation of ERK1/2 and JNK. These results suggest that Sal. B may have therapeutic potential for the prevention of atherosclerosis related inflammation.
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Tsai, Ming Horng, and 蔡明宏. "CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/33gm75.
Full textAbstract:
博士長庚大學
臨床醫學研究所
106
Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expressionand cell migration of HASMCs, which was inhibited by transfection with siRNA of P47phox, Nox2, Nox4, p65, angiotensin II type I receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and P47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9 dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting OC and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.
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Weng, Wen-Yu, and 翁郁雯. "The Effects of Ganoderma lucidum Polysaccharides on the Proliferation of Cultured Human Aortic Smooth Muscle Cells and the Neointimal Hyperplasia of Mice." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/46911078050653441747.
Full textAbstract:
碩士國立臺灣大學
解剖學暨生物細胞學研究所
98
Vascular smooth muscle cell (VSMCs) proliferation, triggered by inflammatory response of the vascular wall, is considered to be the key event in the development of atherosclerosis and restenosis. Therefore, the identification of novel compounds with combined anti-inflammatory and anti-proliferative properties may be an attractive therapeutic strategy for the prevention of cardiovascular diseases. A glucan-containing extract of Ganoderma lucidum-derived polysaccharides (EORP) has been proposed to possess immuno-modulatory functions and antitumor activities. However, its effects on the proliferation of VSMCs and the relative mechanisms remain unclear. In this study we aimed to examine the effects of EORP on the PDGF (platelet-derived growth factor)-treated human aortic smooth muscle cells (HASMCs) and neointimal hyperplasia in endothelia-denuded femoral artery of mice. EORP treatment inhibited proliferation of PDGF-treated HASMCs demonstrated by cell count, MTT (3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and 5-bromodeoxyuridine (BrdU) incorporation (MTT data, control:1; PDGF:1.38±0.01; PDGF+10 μg/mL EORP:1.03±0.02; cell count data, control:15.45±0.65×103; PDGF:23.25±0.05×103; BrdU data: control: 0.02±0.01; PDGF: 0.08±0.01; PDGF+10 μg/mL EORP: 0.02±0.00). Flow cytometry analysis showed EORP altered cell cycle distribution. EORP decreased cell proportion of S phase and increased cell proportion of G0/G1 phase (G0/G1 phase, contol:89.1±1.4 %; PDGF: 80.4±4.3 %, PDGF+10 μg/mL EORP: 85.7±3.8 %; S phase, control:1.7±0.9 %; PDGF: 5.8±2.8 %, PDGF+10 μg/mL EORP: 3.4±2.5 %). Western blot analysis demonstrated EORP downregulated PDGF-induced cyclin D1, cyclin E, CDK2 expression and upregulated p27 expression. Phosphorylation studies of MAPKs demonstrated that EORP suppressed PDGF-induced JNK/SAPK (stress-activated protein kinase) and p38 phosphorylation. For in vivo studies, oral EORP treatment reduces neointimal hyperplasia in endothelia-denuded femoral artery of mice (I/M ratio, endothelial denudation: 1.46±0.30; EORP+endothelial denudation: 0.67±0.03) and downregulated cell proliferation marker-PCNA (proliferating cell nuclear antigen) expression (PCNA positive cells ratio, endothelial denudation: 79.44±3.80 %; EORP+endothelial denudation: 60.78±2.65%). These results suggest that EORP may provide an effective novel approach to prevent vascular diseases through inhibition of vascular smooth muscle cells proliferation.
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Lai, Jing-Yang, and 賴景揚. "The ethyl acetate layer from Phellinus linteus and inotilone inhibit TNF-α-induced proliferation, migration, and invasion in human aortic smooth muscle cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/01313893122758132327.
Full textAbstract:
碩士中國醫藥大學
中國藥學暨中藥資源學系碩士班
99
The migration of vascular smooth muscle cells (VSMC) from the tunica media to the subendothelial region is a key event in the development of atherosclerosis and restenosis. The increased expression and activities of matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of cardiovascular disease. Type Ⅳ collagenases or gelatinases (MMP-2 and MMP-9) are critical for the development of arterial lesions via its regulation of both VSMC migration and proliferation. Inotilone is a major component of Phellinus Linteus (PL) which has been used as a traditional medicinal mushroom in China, Korea, Japan and other Asian countries. Several studies demonstrated to exhibit anti-bacterial, anti-tumour, anti-fibrotic, antimutagenic, anti-oxidant and anti-inflammatory functions, as well as stimulating humoral and cell-mediated immunity in several studies. In this study, we investigated the effects of the ethyl acetate layer from PL (PLEA) and inotilone, an active component of PL, on tumor necrosis factor-α (TNF-α)-induced cell proliferation and migration in human aortic smooth muscle cells (HASMCs). The cytotoxicity of PLEA and inotilone on HASMCs was measured by the MTT assay method. The migration and Invasion assay showed that PLEA and Inotilone effectively inhibited TNF-α-induced migration and invasion of HASMCs as compared with the control group in a dose-dependent manner. To explain this inhibitory effect, PLEA and Inotilone were assayed by gelatin zymography and Western blot. In present study, HASMCs treated with 100 ng/mL TNF-α were found to increase expression of MMP-2, MMP-9, and phosphorylation of FAK, ERK, JNK, p38, and IκB, but decreased TIMP-1 and TIMP-2. Treatment of HASMCs with PLEA and inotilone attenuated TNF-α-induced the expression of MMP-2, MMP-9, and phosphorylation of FAK, ERK, JNK, p38, and IκB, but enhanced TIMP-1 and TIMP-2. These results suggest that PLEA and inotilone might effectively suppress TNF-α-induced HASMC migration and proliferation and represent potential agents for the prevention of vascular disorders.
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Lin, Chia-Ying, and 林佳穎. "The effects of Ganoderma lucidum polysaccharides regulated Interleukin-1 expression in Lipopolysaccharides-treated mice and human aortic smooth muscle cells and its mechanisms." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/78991847249426860125.
Full textAbstract:
碩士國立臺灣大學
解剖學暨生物細胞學研究所
96
Ganoderma lucidum (Reishi, Ling-Zhi), a popular home remedy, has been known for its beneficial activities in human health and longevity for centuries. Accumulated studies attempting to understand the role of Reishi in regulating various body functions revealed that the crude or purified components of Reishi extracts possess anti-tumor and immunomodulating activities. A glucan-containing extract of Reishi-derived polysaccharides (EORP; F3) in human macrophages exerts immuno-modulating activities by stimulating the expression of interleukin-1β (IL-1β), a key mediator in chronic vascular inflammatory response. In the present study, we used F3 to test its functional role in LPS-treated smooth muscle cells, which play a key role in atherogenesis and restenosis. LPS treatment increased intercellular cell adhesion molecule-1 (ICAM-1) expression in a time- and dose-dependent manner in human aortic smooth muscle cells (HASMCs). Pretreatment with F3 significantly suppressed the LPS-induced expression of ICAM-1, and the effect was mediated by the inhibition of ERK phosphorylation. F3 also significantly reduced the binding of the human monocytic cell line, U937, to LPS-treated HASMCs. In addition, F3 could regulate the expression of IL-1βand IL-1 receptor antagonist (IL-1 Ra) in LPS-treated HASMCs as well as in plasma and vascular wall in LPS-treated C57BL6 mice by ELISA and Western blotting. These results suggest that F3 may play important roles in the protection of atherosclerosis and inflammatory responses.
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Wu, Meng-Ling, and 鄔孟陵. "The expression of extracellular matrix synthetic enzymes, lysyl oxidase and prolyl 4-hydroxylase, in human abdominal aortic aneurysm-derived vascular smooth muscle cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/70367520100843730011.
Full textAbstract:
碩士國立成功大學
細胞生物及解剖學研究所
95
Abdominal aortic aneurysm (AAA) occurs in 3~9% of the population over 65 years of age and exhibits a high mortality rate of 50% to 70% when rupture. Destruction of medial wall by proteinases and smooth muscle cell depletion are prominent characteristics of AAA. The mechanisms of extracellular matrix (ECM) degradation have been examined extensively, but much less are known about the regulatory mechanisms of ECM biosynthesis in AAA. Vascular smooth muscle cells (VSMCs) are responsible for synthesizing ECM proteins and maintaining structural integrity of the vascular wall. Lysyl oxidase (Lox), the enzyme initiating the covalent crosslinking of collagen and elastin in the extracellular space, and prolyl 4-hydroxylases (P4H), the rate-limiting enzyme for collagen biosynthesis, are key enzymes regulating ECM biosynthesis and repair. Reactive oxygen species (ROS) have been shown to be involved in the pathogenesis of AAA. Previous studies in our lab indicated that AAA-derived VSMCs exhibited greater capability of ROS production and higher NAD(P)H oxidase activity upon angiotensin II (Ang II) stimulation. Therefore, we hypothesize that increased ROS may modulate Lox and P4H expression in AAA-derived VSMCs. This study used cultured VSMCs derived from AAA specimens as an in vitro model with VSMC derived from the punctured ascending aortae at coronary artery bypass graft (CABG) surgery as control. The mRNA expression of three P4H-α subunits (α1, α2 and α3), P4H-β, and Lox was examined by semi-quantitative RT-PCR. In addition, P4H-β protein expression was examined by immunoblotting. At tissue level, no difference in P4H-β expression was detected between CABG and AAA specimens. In cultured cells, no significant differences in mRNA expression were detected between AAA- and CABG-derived VSMCs for all P4H subunits and Lox. Ang II treatment had no effects on P4H-α1, P4H-α2, P4H-α3, P4H-β or Lox mRNA expression in both AAA- and CABG-derived VSMCs. In human aortic VSMCs, LY83583, a superoxide anion-generating agent, decreased P4H-α1 mRNA expression. In addition, peroxynitrite, an ROS formed by the reaction between superoxide and nitric oxide, decreased P4H-β expression in a dose-dependent manner whereas H2O2 had no effect. These results suggest that oxidative stress may contribute to decreased P4H subunit expression in VSMCs but Ang II does not appear to be the stimulant under current experimental conditions. Further studies are needed to verify whether the expression of Lox and P4H subunits is affected in human AAA specimens.
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Yen, Hui-Tzu, and 顏惠芷. "The Effects of Salvianolic Acid B on the Expression of Cytokines in oxLDL-Induced Human Aortic Smooth Muscle Cells or Apo E Deficient Mice." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/06125171346054596475.
Full textAbstract:
碩士國立陽明大學
解剖暨細胞生物學研究所
89
Atherosclerosis is the major contributor to the pathogenesis of myocardial and cerebral infarction. In the development of atherosclerotic lesions, three basic processes occur: (1) invasion of the artery wall by leukocytes, particularly monocytes and T-lymphocytes; (2) smooth muscle phenotypic modulation, proliferation, and synthesis of extracellular matrix; and (3) intracellular (macrophage and smooth muscle cells) lipoprotein uptake and lipid accumulation. The presence of inflammatory cells in the vascular wall suggests that atherosclerosis is an inflammatory and immune disease. Interleukin-1 (IL-1), an inflammatory mediator, has been implicated as a cytokine in the development and clinical sequelae of atherosclerosis. Fully understanding of the role of IL-1 and IL-1 receptor antagonist (IL-1ra) involved in the mechanism of atherosclerotic development is critically important. Oxidized low-density lipoprotein (oxLDL) is also involved in the development of atherosclerosis and antioxidants may protect component cells in the vessels against oxLDL-induced damages. Salvia miltiorrhiza (SM) is a herb widely used in the treatment of cardiovascular disorders and contains Salvianolic acid B (Sal. B), a potent antioxidant. In the present study, we examined the effects of Sal. B on the cytotoxicity and the expression of IL-1 and IL-1ra in oxLDL-treated human aortic smooth muscle cells (HASMCs). OxLDL (40 and 60 g cholesterol/ml) induced HASMCs death was time-and dose-dependent, whereas native LDL had no effect. HASMCs treated with 60 g/ml oxLDL for 8 hours increased annexin V binding, chromosome condensation and caspase-3 activation. OxLDL treatment also increase the expression of IL-1 and IL-1ra as well as the activation of NF-B and AP-1. Pretreatment of HASMCs with Sal. B (1 to 10 g/ml, 24 hours) attenuated the cytotoxicity, apoptosis, the expression of IL-1 and IL-1ra induced by oxLDL. These results demonstrate that Sal. B has anti-inflammatory and anti-atherosclerotic properties. The new mechanism of action of Sal. B, in addition to their previously reported inhibition of LDL oxidation, may help explain their efficacy in the treatment of atherosclerosis.