Endothelial dysfunction in aged Trx-deficient mice.

描述（由申请人提供）：内皮功能障碍是心脏缺血再灌注损伤的潜在分子机制，并已被证明影响心肌梗死的梗死面积。心肌梗塞和其他冠心病是主要的健康问题，仅在美国就特别影响数百万老年人。这种损伤部分是对氧化应激引起的内皮功能障碍的反应，当血管再灌注缺血心脏组织时，氧化应激会增加。因此，调节心脏氧化还原环境的药物可能对治疗冠心病有用。因此，我们的实验室一直在表征硫氧还蛋白（Trx），这是一种内源性酶，可以减少氧化应激并再生因氧化而失活的蛋白质。结合这项研究，我们开发了两种改变Trx活性的转基因小鼠系：一种（Trx- tg）过度表达Trx蛋白，而另一种（dnTrx-Tg）表达非活性Trx，因此可以作为条件Trx敲除。当我们对这些独特的小鼠进行表征时，我们发现衰老的TrxTg小鼠在缺血-再灌注（I/R）反应中可以防止心肌梗死，而那些缺乏Trx的小鼠，如野生型，会遭受广泛的心肌损伤。因此，我们假设Trx活性水平的增加可以提供对内皮功能障碍的保护。这一假设导致了本提案的具体目的：目的1将确定Trx在I/R损伤引起的内皮功能障碍中的作用；目标2将探讨这些影响的潜在机制；和Aim 3将确定Trx是否增加线粒体超氧化物歧化酶的表达，作为防止内皮功能障碍的一个因素。该项目的结果将有助于我们了解动脉粥样硬化等心血管疾病中内皮细胞功能障碍，并推动Trx作为一种真正的新型治疗方法的发展，因为外源性添加的Trx被内皮细胞大量吸收。

DESCRIPTION (provided by applicant): Endothelial dysfunction is an underlying molecular mechanism in ischemia-reperfusion injury of the heart, and has been shown to affect infarct size in myocardial infarction. Myocardial infarction and other coronary heart disease are major health problem that especially affects millions of older people in the United States alone. This damage occurs in part in response to endothelial dysfunction caused by oxidative stress, which increases when blood vessels reperfused ischemic heart tissue. Thus, agents that modulate the redox environment of the heart are potentially useful for treating coronary heart disease. For this reason, our laboratory has been characterizing thioredoxin (Trx), an endogenous enzyme that can reduce oxidative stress and regenerate proteins that have been inactivated by oxidation. In conjunction with this research, we developed two transgenic mouse lines that have altered Trx activity: one (Trx-Tg) overexpresses the protein, whereas the other (dnTrx-Tg) expresses an inactive Trx and thus acts as a conditional Trx knockout. As we characterized these unique mice, we discovered that aged TrxTg 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 activity can afford protection against endothelial dysfunction. This hypothesis leads to the Specific Aims of this proposal: Aim 1 will establish the role of Trx in endothelial dysfunction arising from I/R injury; Aim 2 will explore potential mechanisms of these effects; and Aim 3 will determine whether Trx increases the expression of mitochondrial superoxide dismutase as a contributor to protection against endothelial dysfunction. The outcomes of this project will contribute to our understanding of endothelial cell dysfunction in cardiovascular diseases such as atherosclerosis, and propel the development of Trx as a real novel therapeutic approach to treat cardiovascular disease as exogenously added Trx is avidly taken up by endothelial cells.