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Academic literature on the topic 'GATA4 Hypertrophie Herz'
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Journal articles on the topic "GATA4 Hypertrophie Herz"
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Liang, Qiangrong, Russell J. Wiese, Orlando F. Bueno, Yan-Shan Dai, Bruce E. Markham, and Jeffery D. Molkentin. "The Transcription Factor GATA4 Is Activated by Extracellular Signal-Regulated Kinase 1- and 2-Mediated Phosphorylation of Serine 105 in Cardiomyocytes." Molecular and Cellular Biology 21, no. 21 (2001): 7460–69. http://dx.doi.org/10.1128/mcb.21.21.7460-7469.2001.
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ABSTRACT The zinc finger-containing transcription factor GATA4 has been implicated as a critical regulator of multiple cardiac-expressed genes as well as a regulator of inducible gene expression in response to hypertrophic stimulation. Here we demonstrate that GATA4 is itself regulated by the mitogen-activated protein kinase signaling cascade through direct phosphorylation. Site-directed mutagenesis and phospho-specific GATA4 antiserum revealed serine 105 as the primary site involved in agonist-induced phosphorylation of GATA4. Infection of cultured cardiomyocytes with an activated MEK1-expressing adenovirus induced robust phosphorylation of serine 105 in GATA4, while a dominant-negative MEK1-expressing adenovirus blocked agonist-induced phosphorylation of serine 105, implicating extracellular signal-regulated kinase (ERK) as a GATA4 kinase. Indeed, bacterially purified ERK2 protein directly phosphorylated purified GATA4 at serine 105 in vitro. Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor). Phosphorylation of serine 105 also modestly enhanced the DNA binding activity of bacterially purified GATA4. Finally, induction of cardiomyocyte hypertrophy with an activated MEK1-expressing adenovirus was blocked with a dominant-negative GATA4-engrailed-expressing adenovirus. These results suggest a molecular pathway whereby MEK1-ERK1/2 signaling regulates cardiomyocyte hypertrophic growth through the transcription factor GATA4 by direct phosphorylation of serine 105, which enhances DNA binding and transcriptional activation.
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Ahmadvand, Shiva, Ali Osia, Anna Meyfour, and Sara Pahlavan. "Gender-specific characteristics of hypertrophic response in cardiomyocytes derived from human embryonic stem cells." Journal of Cardiovascular and Thoracic Research 13, no. 2 (2021): 146–55. http://dx.doi.org/10.34172/jcvtr.2021.32.
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Introduction: Gender-specific phenotypes of the heart were reported with respect to both physiology and pathology. While most differences were associated with the sex hormones, differential expression of genes received special attention, particularly X-Y chromosomes’ genes. Methods: Here, we compared cardiogenesis by gene expression analysis of lineage specific markers and X-Y chromosomes’ genes, during in vitro differentiation of XY and XX human embryonic stem cells (hESC), in a hormone-free setup. Results: Downregulation of pluripotency marker (NANOG) and upregulation of cardiac mesoderm and progenitor markers (GATA4, TBX5, NKX2.5, ISL1) was remained temporally similar in differentiating XY and XX hESCs. Isoproterenol treatment of XY and XX hESC-derived cardiomyocytes (hESCCM) induced hypertrophy in a sex-specific manner, with female cardiomyocytes showing response at higher isoproterenol concentration and a later time point of differentiation. Interestingly, KDM5C as an X-linked gene, was markedly upregulated in both hypertrophied male and female cardiomyocytes. Conclusion: Collectively, our results indicated a temporally identical cardiogenesis, but more susceptibility of XY hESC-CM to hypertrophic stimulus in a hormone-free condition.
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Lu, Chieh-Hsiang, Chia-Yao Shen, Dennis Jine-Yuan Hsieh, et al. "Deep ocean minerals inhibit IL-6 and IGFIIR hypertrophic signaling pathways to attenuate diabetes-induced hypertrophy in rat hearts." Journal of Applied Physiology 127, no. 2 (2019): 356–64. http://dx.doi.org/10.1152/japplphysiol.00184.2019.
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We previously reported that deep sea water (DSW) prolongs the life span of streptozotocin (STZ)-induced diabetic rats by the compensatory augmentation of the insulin like growth factor (IGF)-I survival signaling and inhibition of apoptosis. Here, we investigated the effects of DSW on cardiac hypertrophy in diabetic rats. Cardiac hypertrophy was induced in rats by using STZ (65 mg/kg) administered via IP injection. DSW was prepared by mixing DSW mineral extracts and desalinated water. Different dosages of DSW-1X (equivalent to 37 mg Mg2+·kg−1·day−1), 2X (equivalent to 74 mg Mg2+·kg−1·day−1) and 3X (equivalent to 111 mg Mg2+·kg−1·day−1) were administered to the rats through gavage for 4 wk. Cardiac hypertrophy was evaluated by the heart weight-to-body weight ratio and the cardiac tissue cross-sectional area after hematoxylin and eosin staining. The protein levels of the cardiac hypertrophy signaling molecules were determined by Western blot. Our results showed that the suppressive effects of the DSW treatment on STZ-induced cardiac hypertrophy were comparable to those of MgSO4 administration and that the hypertrophic marker brain natriuretic peptide (BNP) was decreased by DSW. In addition, DSW attenuated both the eccentric hypertrophy signaling pathway, IL-6-MEK-STAT3, and the concentric signaling pathway, IGF-II-PKCα-CaMKII, in DM rat hearts. The cardiac hypertrophy-associated activation of extracellular signal-regulated kinase (ERK) and the upregulation of the transcription factor GATA binding protein 4 (GATA4) were also negated by treatment with DSW. The results from this study suggest that DSW could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy. NEW & NOTEWORTHY Deep sea water, containing high levels of minerals, improve cardiac hypertrophy in diabetic rats through attenuating the eccentric signaling pathway, IL-6-MEK5-STAT3, and concentric signaling pathway, IGF2-PKCα-CaMKII. The results from this study suggest that deep sea water could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.
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Harrison, Brooke C., Charles R. Roberts, David B. Hood, et al. "The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression." Molecular and Cellular Biology 24, no. 24 (2004): 10636–49. http://dx.doi.org/10.1128/mcb.24.24.10636-10649.2004.
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ABSTRACT Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.
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Kim, Tae-gyun, Junqin Chen, Junich Sadoshima, and Youngsook Lee. "Jumonji Represses Atrial Natriuretic Factor Gene Expression by Inhibiting Transcriptional Activities of Cardiac Transcription Factors." Molecular and Cellular Biology 24, no. 23 (2004): 10151–60. http://dx.doi.org/10.1128/mcb.24.23.10151-10160.2004.
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ABSTRACT Mice with a homozygous knockout of the jumonji (jmj) gene showed abnormal heart development and defective regulation of cardiac-specific genes, including the atrial natriuretic factor (ANF). ANF is one of the earliest markers of cardiac differentiation and a hallmark for cardiac hypertrophy. Here, we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. JMJ represses the Nkx2.5- or GATA4-dependent activation of the reporter genes containing the ANF promoter-enhancer or containing the Nkx2.5 or GATA4-binding consensus sequence. JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. Using mutational analyses, we mapped the protein-protein interaction domains in JMJ, Nkx2.5, and GATA4. We identified two DNA-binding sites of JMJ in the ANF enhancer by gel mobility shift assays. However, these JMJ-binding sites do not seem to mediate ANF repression by JMJ. Mutational analysis of JMJ indicates that the protein-protein interaction domain of JMJ mediates the repression of ANF gene expression. Therefore, JMJ may play important roles in the down-regulation of ANF gene expression and in heart development.
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Oka, Toru, Yan-Shan Dai та Jeffery D. Molkentin. "Regulation of Calcineurin through Transcriptional Induction of the calcineurin Aβ Promoter In Vitro and In Vivo". Molecular and Cellular Biology 25, № 15 (2005): 6649–59. http://dx.doi.org/10.1128/mcb.25.15.6649-6659.2005.
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ABSTRACT The calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway has been shown to be of critical importance in regulating the growth response of cardiac myocytes. We have previously demonstrated that calcineurin Aβ (CnAβ) mRNA and protein are increased in response to growth stimulation, although the precise regulatory mechanism underlying CnAβ upregulation is not clear. Here, we isolated the mouse CnAβ promoter and characterized its responsiveness to growth stimuli in vitro and in vivo. A 2.3-kb promoter fragment was strongly activated by phenylephrine and endothelin-1 stimulation and by cotransfection with constitutively active CnA, NFATc4, and GATA4. Using chromatin immunoprecipitation, sequence regions were identified within the 2.3-kb promoter that associated with NFAT and GATA4, as well as with acetylated histone H3, following agonist stimulation. Consistent with the chromatin immunoprecipitation experiments, deletion of the distal half of the CnAβ promoter severely reduced NFAT, GATA4, and hypertrophic agonist-mediated activation. To investigate in vivo activity, we generated β-galactosidase (LacZ) containing transgenic mice under the control of the CnAβ 2.3-kb promoter. CnAβ-LacZ mice showed expression in the heart that was cyclosporine sensitive, as well as expression in the central nervous system and skeletal muscle from early embryonic stages through adulthood. CnAβ-LacZ mice were subjected to cardiac pressure overload stimulation and crossbreeding with mice containing cardiac-specific transgenes for activated calcineurin and NFATc4, which revealed inducible expression in the heart. These results indicate that the CnAβ 2.3-kb promoter is specifically activated by hypertrophic stimuli through a positive feedback mechanism involving NFAT and GATA4 transcription factors, suggesting transcriptional induction of CnAβ expression as an additional means of regulating calcineurin activity in the heart.
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Panguluri, Siva K., Jared Tur, Jutaro Fukumoto, et al. "Hyperoxia-induced hypertrophy and ion channel remodeling in left ventricle." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 12 (2013): H1651—H1661. http://dx.doi.org/10.1152/ajpheart.00474.2012.
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Ventricular arrhythmias account for high mortality in cardiopulmonary patients in intensive care units. Cardiovascular alterations and molecular-level changes in response to the commonly used oxygen treatment remains unknown. In the present study we investigated cardiac hypertrophy and cardiac complications in mice subjected to hyperoxia. Results demonstrate that there is a significant increase in average heart weight to tibia length (22%) in mice subjected to hyperoxia treatment vs. normoxia. Functional assessment was performed in mice subjected to hyperoxic treatment, and results demonstrate impaired cardiac function with decreased cardiac output and heart rate. Staining of transverse cardiac sections clearly demonstrates an increase in the cross-sectional area from hyperoxic hearts compared with control hearts. Quantitative real-time RT-PCR and Western blot analysis indicated differential mRNA and protein expression levels between hyperoxia-treated and control left ventricles for ion channels including Kv4.2 (−2 ± 0.08), Kv2.1 (2.54 ± 0.48), and Scn5a (1.4 ± 0.07); chaperone KChIP2 (−1.7 ± 0.06); transcriptional factors such as GATA4 (−1.5 ± 0.05), Irx5 (5.6 ± 1.74), NFκB1 (4.17 ± 0.43); hypertrophy markers including MHC-6 (2.17 ± 0.36) and MHC-7 (4.62 ± 0.76); gap junction protein Gja1 (4.4 ± 0.8); and microRNA processing enzyme Drosha (4.6 ± 0.58). Taken together, the data presented here clearly indicate that hyperoxia induces left ventricular remodeling and hypertrophy and alters the expression of Kv4.2 and MHC6/7 in the heart.
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Purcell, Nicole H., Dina Darwis, Orlando F. Bueno, Judith M. Müller, Roland Schüle, and Jeffery D. Molkentin. "Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes." Molecular and Cellular Biology 24, no. 3 (2004): 1081–95. http://dx.doi.org/10.1128/mcb.24.3.1081-1095.2004.
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ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.
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Leigh, Robert S., and Bogac L. Kaynak. "Vitamin A as a Transcriptional Regulator of Cardiovascular Disease." Hearts 1, no. 2 (2020): 126–45. http://dx.doi.org/10.3390/hearts1020013.
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Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues.
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Prakash, Ajay, Aaron M. Udager, David A. Saenz, and Deborah L. Gumucio. "Roles for Nkx2–5 and Gata3 in the ontogeny of the murine smooth muscle gastric ligaments." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 4 (2014): G430—G436. http://dx.doi.org/10.1152/ajpgi.00360.2013.
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The gastric ligaments are superficial cord-like structures, located on the lesser curvature of the stomach, that extend from the pylorus to the esophagus. These ligaments have been documented in a wide variety of mammalian species, including humans, but their composition and ontogeny is unexplored. Here, we demonstrate that, during ontogeny, the gastric ligaments are first visible as extensions from a C-shaped domain of Gata3-expressing cells that surround the future pylorus; this domain will later give rise to the pyloric outer longitudinal muscle (OLM). The open ends of the C are located ventrally, and, beginning at embryonic day (E) 13.5, the ligaments grow anteriorly from these points. Whereas most other ligaments of the stomach are neurovascular in nature, the gastric ligaments are composed of smooth muscle cells that mature between E14.5 and E16.5. The gastric ligaments coexpress the transcription factors Gata3, Nkx2–5, and Sox9, and germline loss of Gata3 or conditional deletion of Nkx2–5 abrogates Sox9 expression and impairs gastric ligament smooth muscle development; similar phenotypes were previously seen in the OLM. In accord with this molecular contiguity between the OLM and gastric ligaments, three-dimensional image reconstruction highlights physical contiguity between these smooth muscle structures, suggesting that they may work together as a unit to control flexure of the pyloric region, a function similar to the ligament of Treitz at the duodenojejunal junction. These findings may have implications for our understanding of normal pyloric sphincter function, as well as the common human congenital pathology idiopathic hypertrophic pyloric stenosis.
Dissertations / Theses on the topic "GATA4 Hypertrophie Herz"
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Wilken, Andre. "Der Transkriptionsfaktor GATA4 und seine Rolle in der Entwicklung kardialer Hypertrophie." Doctoral thesis, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7C98-D.
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Die Rolle von GATA4 für die Entwicklung einer Hypertrophie und seine Regulation in Abhängigkeit von der Last sind im menschlichen Herzen im Gegensatz zu den zahlreichen tierexperimentellen Ansätzen bislang nicht gezielt untersucht worden.
Die vorliegende Arbeit sollte zeigen, wie biomechanische Last im menschlichen Herzen die Expression von GATA4 und seine Phosphorylierung an einer aktivierenden Phosphorylierungsstelle (Serin-105) reguliert. Hierfür wurde der Einfluss eines chronischen Lastzustandes, hervorgerufen durch eine Aortenstenose, ebenso wie der eines akuten Lastzustandes durch Steigerung der Vor- und Nachlast von Muskelstreifen im Organbad auf die Expression von GATA4 untersucht. Die Muskelstreifen stammten dabei sowohl aus gesundem Myokard (Vorhofmyokard bei normaler Pumpfunktion) als auch aus vorgeschädigtem Myokard (insuffizientes Ventrikelmyokard).
Im ersten Teil wurde dargestellt, dass eine chronische Nachlasterhöhung zu einer signifikanten Zunahme der mRNA- und Proteinexpression sowie der Phosphorylierung von GATA4 führte. Während die mRNA- und Proteinexpression in vivo lastabhängig reguliert zu sein scheinen, zeigte die GATA4-Phosphorylierung eine signifikante Korrelation mit der kardialen Pumpfunktion. Die messbare Aktivitätssteigerung durch Phosphorylierung unterstützt dabei die Idee von GATA4 als Mediator ventrikulärer Hypertrophie zum Erhalt der kardialen Pumpfunktion.
Unter der Auswirkung akuter Last stellte sich hingegen ein heterogenes Bild dar. Eine Steigerung der Gesamtexpression war nicht nachzuweisen, aber ein signifikanter Dehnungseffekt im suffizienten atrialen Myokard, welcher offensichtlich durch eine Abschwächung einer zeitabhängigen Proteindegradation zu Stande kommt. Die Abnahme der GATA4-Expression über die Zeit war unter Einwirkung akuter Last deutlich vermindert aber noch vorhanden. Das Ubiquitin-Proteasom-System ist daran eindeutig beteiligt, da durch den Ubiquitin-Isopeptidase-Inhibitor Δ12-PGJ2 der Abbau von GATA4 vermindert werden konnte.