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

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，850万人经历心肌梗塞（AHA 2006）。美国老年人患冠心病的风险很高。改善预后需要限制心肌缺血再灌注（I/R）损伤，以保护心肌功能。心脏内皮细胞与心肌细胞非常接近，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术后心肌梗死的重要因素。研究表明，I/R时心脏内皮细胞凋亡先于心肌细胞凋亡。我们最近开发了缺乏功能性硫氧还蛋白（dnTrx-Tg）的转基因小鼠，这是一种内源性氧化还原活性抗氧化蛋白。我们也培育了表达更高水平Trx （Trx- tg）的小鼠。通过这些Trx功能获得和功能丧失的小鼠，我们发现衰老的Trx- tg小鼠在缺血再灌注（I/R）反应中可防止心肌梗死，而Trx缺乏的小鼠，如野生型，则会遭受广泛的心肌损伤。因此，我们假设增加的Trx水平可以提供对内皮细胞凋亡的保护。这一假设导致了本提案的具体目的：目的1将确定Trx在NRG1¿/ErbB4信号介导的内皮细胞凋亡中的作用；目的2将探讨这些作用的潜在机制，因为它与Nox4激活、eNOS通过VEGF表达有关；和Aim 3将确定Trx水平的升高是否抑制I/R中保护肌细胞凋亡的凋亡信号调节激酶（ASK1）。本项目的结果将有助于我们了解硫氧还蛋白在内皮细胞凋亡中的保护作用，这可能会导致基于内皮治疗心肌梗死的新方法。

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.