Kinases-mediated SUMOylation in Diabetic Cardiomyopathy

糖尿病心肌病中激酶介导的 SUMO 化

• 批准号: 7373477
• 负责人: Jun-Ichi Abe
• 金额: $ 51.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373477
• 关键词: ATP2A2; Abbreviations; Adenovirus Vector; Adenoviruses; Adrenergic Receptor; Angiotensin II; Animals; Apoptosis; Appendix; Area; Arts; Binding; Biochemical; Blood Glucose; Ca(2+)-Transporting ATPase; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cellular biology; Chloride Ion; Chlorides; Clinical; Clinical Research; Collaborations; Complex; Condition; Constriction procedure; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; Data; Depth; Diabetes Mellitus; Dominant-Negative Mutation; Down-Regulation; Elevation; Endoplasmic Reticulum; Fasting; Feedback; Functional disorder; Gene Targeting; Genetic Transcription; Glucose; Goals; Heart; Heart Diseases; Heart failure; Hydrogen Peroxide; Hyperglycemia; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Insulin-Like Growth Factor I; Intervention; Ischemia; Isoproterenol; Left; Left Ventricular Function; Left Ventricular Remodeling; Ligase; MAPK7 gene; Mediating; Methods; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Muscle Cells; Myocardial Infarction; Numbers; Outcome; PDE3A gene product; Patients; Perioperative; Phosphorylation; Phosphotransferases; Physiological reperfusion; Play; Protein Isoforms; Protein Kinase; Reactive Oxygen Species; Reagent; Renin-Angiotensin System; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Research Personnel; Ribosomal Protein S6 Kinase; Risk; Risk Factors; Role; Seasons; Signal Transduction; Streptozocin; System; Tetrazolium; Transcription Repressor/Corepressor; Transcriptional Regulation; Transduction Gene; Transgenic Mice; Transgenic Organisms; Ubiquitin; Ventricular; Ventricular Function; Viral Vector; Work; base; diabetes risk; diabetic; diabetic cardiomyopathy; extracellular; in vivo; inhibitor/antagonist; injured; innovation; mortality; non-diabetic; novel; novel therapeutics; protein inhibitor of activated STAT 1; receptor expression; small molecule

DESCRIPTION (provided by applicant): Perioperative myocardial infarction (MI) remains a significant clinical problem and diabetes is an independent risk factor for both mortality and morbidity after MI. A number of clinical studies have shown that the post-MI left ventricular function is significantly worse in diabetic compared with non- diabetic patients. However, what is lacking is a plausible relationship between diabetes and any of the known regulators of myocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Recently, we have demonstrated that a novel signaling between phosphodiesterase 3A (PDE3A) and inducible cAMP early repressor (ICER), the PDE3A-ICER feedback loop, is a likely mechanism determining the fate of injured myocytes. Our recent preliminary data to be presented in this proposal indicate that ERK5, an atypical mitogen activated protein kinase with transcriptional activity, regulates the PDE3A-ICER feedback loop and that the ERK5 transcriptional activity itself is subjected to down regulation by a hyperglycemia- dependent small ubiquitin-related modification (SUMO). p90RSK, a kinase activated in diabetes, increases ERK5-SUMOylation and inhibits its transcriptional activity. Our working hypothesis is that inhibition of ERK5 transcriptional activity in diabetic heart by p90RSK-mediated ERK5-SUMOylation results in a proapoptotic condition likely to contribute to poor post-MI cardiac ventricular function. The specific aims are: Aim 1: Determine the role of p90RSK activation on streptozotocin-induced exacerbation of left ventricular remodeling after MI, in vivo. Aim 2. Determine the role of p90RSK-ERK5 axis on streptozotocin- induced exacerbation of LV remodeling after MI in vivo. Aim 3: Determine the molecular mechanisms by which p90RSK functions as an inhibitor for ERK5 transcriptional activity in cardiomyocytes, in vitro. Aim 4: Determine the role of angiotensin II, reactive oxygen species and high glucose-mediated endogenous p90RSK activation and subsequent ERK5-SUMOylation in PDE3A-ICER feedback loop-mediated apoptosis and inhibition of SERCA2 and 21-adrenergic receptor expression in vitro, and we will investigate the functional significance of the molecular interaction between p90RSK and ERK5 transcriptional regulation through extensive use of adenovirus in an in vitro myocyte ststem. The broad-based experimental approach including the use of various transgenic mice and gene transduction viral vectors should allow us to determine the importance of p90RSK-ERK5 axis in diabetic cardiomyopathy. Moreover, we believe that our novel small molecule specific p90RSK inhibitor should provide a new therapeutic strategy for reducing post- ischemic cardiac dysfunction in diabetics.

描述（由申请人提供）：围手术期心肌梗死（MI）仍然是一个重要的临床问题，糖尿病是心肌梗死后死亡率和发病率的独立危险因素。许多临床研究表明，糖尿病患者心肌梗死后左心室功能明显差于非糖尿病患者。然而，缺乏的是糖尿病和任何已知的肌细胞凋亡调节因子之间的合理关系，已知这些调节因子在心肌梗死后心功能障碍中起重要作用。最近，我们已经证明了磷酸二酯酶3A （PDE3A）和诱导型cAMP早期抑制因子（ICER）之间的一种新的信号传导，即PDE3A-ICER反馈回路，可能是决定受伤肌细胞命运的一种机制。我们最近的初步数据表明，ERK5是一种具有转录活性的非典型有丝分裂原激活蛋白激酶，可调节PDE3A-ICER反馈回路，并且ERK5的转录活性本身受到高血糖依赖性小泛素相关修饰（SUMO）的下调。p90RSK是一种在糖尿病中活化的激酶，可增加ERK5-SUMOylation并抑制其转录活性。我们的工作假设是，通过p90rsk介导的ERK5- sumoylation抑制糖尿病心脏中ERK5的转录活性，导致凋亡前状态可能导致心肌梗死后心室功能不佳。目的1：在体内确定p90RSK激活在链脲佐菌素诱导的心肌梗死后左心室重构加重中的作用。目标2。确定p90RSK-ERK5轴在链脲佐菌素诱导心肌梗死后左室重构加重中的作用。目的3：确定p90RSK在体外心肌细胞中作为ERK5转录活性抑制剂的分子机制。目的4：确定血管紧张素II、活性氧和高糖介导的内源性p90RSK激活和随后的ERK5- sumoylation在体外PDE3A-ICER反馈环介导的细胞凋亡和SERCA2和21-肾上腺素能受体表达抑制中的作用，我们将通过在体外肌细胞系统中广泛使用腺病毒来研究p90RSK和ERK5转录调节之间的分子相互作用的功能意义。广泛的实验方法，包括使用各种转基因小鼠和基因转导病毒载体，应该使我们能够确定p90RSK-ERK5轴在糖尿病性心肌病中的重要性。此外，我们相信我们的新型小分子特异性p90RSK抑制剂将为减少糖尿病患者缺血性心功能障碍提供新的治疗策略。