Protective role of thioredoxin in endothelial apoptosis in the heart in ischemia-

硫氧还蛋白对缺血心脏内皮细胞凋亡的保护作用

• 批准号: 8464781
• 负责人: KUMUDA C DAS
• 金额: $ 35.94万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464781
• 关键词: Age; American; Antioxidants; Apoptosis; Apoptotic; Area; Biological Preservation; Bypass; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Line; Cessation of life; Clinical; Coronary heart disease; Data; Endothelial Cells; Endothelium; Enzymes; ErbB4 gene; Figs - dietary; Foundations; Generations; Heart; Heart Diseases; Human; Infarction; Inhibition of Apoptosis; Ischemia; Lead; Mediating; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neuregulins; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Phosphotransferases; Property; Proteins; Reactive Oxygen Species; Reagent; Reperfusion Injury; Reperfusion Therapy; Risk; Role; Signal Transduction; Symptoms; Testing; Therapeutic; Therapeutic Agents; Thioredoxin; Transgenic Mice; United States; Up-Regulation; Vascular Endothelial Growth Factors; Wild Type Mouse; ZAP-70 Gene; aged; base; experience; gain of function; heart cell; high risk; improved; intravenous injection; loss of function; mortality; myocardial infarct sizing; novel; overexpression; oxidation; prevent; protective effect; receptor; response; therapeutic development

DESCRIPTION (provided by applicant): Cardiovascular disease causes 34% of all deaths in the United States (AHA, 2010) and 17.6 million Americans suffer from coronary heart disease (CHD). Of these, 8.5 million experience myocardial infarction (AHA 2006). Older Americans are at high risk for CHDs. Improved outcomes will require limiting ischemia-reperfusion (I/R) injury to preserve the functional myocardium after MI. Endothelial cells of the heart are in close proximity to cardiomyocytes and essentially regulate myocyte function in pathophysiological conditions. Endothelial and myocyte apoptosis are significant contributors for myocardial infarction following I/R. Studies have shown that endothelial apoptosis precedes myocyte apoptosis in the heart in I/R. We have recently developed transgenic mice that are deficient in functional thioredoxin (dnTrx-Tg), an endogenous redox-active antioxidant protein. We have also generated mice that express higher levels of Trx (Trx-Tg). Using these mice with gain-of-function and loss-of-function of Trx, we discovered that aged Trx-Tg mice are protected against myocardial infarction in response to ischemia-reperfusion (I/R), whereas those deficient in Trx, like wild type, undergo extensive myocardial damage. Thus, we hypothesize that increased levels of Trx can afford protection against endothelial apoptosis. This hypothesis leads to the Specific Aims of this proposal: Aim 1 will determine the role of Trx in endothelial apoptosis due to NRG1¿/ErbB4 signaling; Aim 2 will explore potential mechanisms of these effects as it related to Nox4 activation, eNOS expression via VEGF; and Aim 3 will determine whether increased levels of Trx inhibit apoptosis signal regulating kinase (ASK1) in I/R that protects myocyte apoptosis. The outcomes of this project will contribute to our understanding of the protective role of thioredoxin in endothelial apoptosis, which may lead to novel endothelium-based approaches to treat myocardial infarction.

描述（由申请人提供）：心血管疾病导致美国34%的死亡（AHA，2010），1760万美国人患有冠心病（CHD）。其中，850万人发生心肌梗死（AHA 2006）。美国老年人患冠心病的风险很高。改善预后需要限制缺血再灌注（I/R）损伤，以保护MI后的功能性心肌。心脏的内皮细胞非常接近心肌细胞，并且在病理生理条件下基本上调节心肌细胞的功能。内皮细胞和心肌细胞凋亡是I/R后心肌梗死的重要因素。研究表明，在I/R中，心脏中内皮细胞凋亡先于心肌细胞凋亡。我们最近开发的转基因小鼠，缺乏功能性硫氧还蛋白（dnTrx-Tg），内源性氧化还原活性的抗氧化蛋白。我们还产生了表达更高水平的Trx（Trx-Tg）的小鼠。使用这些小鼠的功能获得和功能丧失的Trx，我们发现，老年Trx-Tg小鼠的心肌梗死缺血再灌注（I/R）的保护，而那些缺乏Trx，像野生型，经历广泛的心肌损伤。因此，我们推测，增加Trx水平可以提供保护，防止内皮细胞凋亡。这一假设导致了本提案的具体目标：目标1将确定Trx在NRG 1？/ErbB 4信号转导引起的内皮细胞凋亡中的作用;目标2将探索这些作用的潜在机制，因为它与Nox 4激活、通过VEGF表达eNOS有关;目标3将确定Trx水平升高是否抑制I/R中保护心肌细胞凋亡的凋亡信号调节激酶（ASK 1）。该项目的结果将有助于我们理解硫氧还蛋白在内皮细胞凋亡中的保护作用，这可能会导致新的基于内皮的方法来治疗心肌梗死。