Improving mitochondrial function to protect against myocardial ischemia/reperfusion

心肌缺血/再灌注(IR)损伤是不良反应的主要临床挑战 心肌缺血、心脏手术或循环骤停后的心血管后果。 众所周知，心肌ATP耗竭是心肌梗死的一个重要特征。 缺血和心力衰竭1。改善心肌能量代谢一直是一个很好的- 已知的目标是保护心脏免受IR损伤，但收效甚微。“ 三磷酸腺苷合成酶是线粒体中产生三磷酸腺苷的关键酶复合体，因此在线粒体中发挥重要作用。 在线粒体功能中起中心作用。三磷酸腺苷合成酶功能缺陷可导致 加重人类疾病，如心肌病和充血性心力衰竭。 然而，我们对能量代谢和线粒体调节的理解 能量需求旺盛的心脏的功能仍然很差。我们最近发现了一种 PPAR-编码一种新的功能未知的线粒体蛋白ES1的靶基因。 初步研究表明，ES1是一种线粒体蛋白，与 三磷酸腺苷合成酶F1区的α和β亚基。我们很兴奋地发现ES1的工作方式是 一种通过增加ATP合成和抑制ATP合成来促进ATP产生的增强剂 水解液。然而，目前尚不清楚ES1是否类似地调节了细胞内的ATP生产 心脏受心肌IR的影响。有趣的是，我们的初步研究显示ES1 患者和小鼠心肌IR损伤后，心脏蛋白质水平均降低。 基于对条件转基因和基因打靶小鼠品系的初步研究，我们 假设ES1是保护心脏的新治疗靶点 心肌IR通过其在促进心脏能量产生/储备中的作用而发挥作用。至 检验这一中心假设，我们将首先定义ES1作为内源性 三磷酸腺苷合成酶的调节因子和线粒体结构/功能的决定因素 心。然后我们将确定转基因和腺病毒相关病毒介导的 ES1在心脏过表达对心肌IR损伤的保护作用 在调节能量代谢方面的作用。这些研究将提供新的见解，了解如何 操控能量代谢，保护心脏免受心肌缺血再灌注损伤。 此外，这些新的基础科学发现将在以下方面产生更广泛的影响 与其他器官和组织有关的疾病。

Myocardial ischemia/reperfusion (IR) injury is the main clinical challenge of adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. It is well established that myocardial ATP depletion is a key feature of myocardial ischemia and heart failure1. Improving myocardial energy metabolism has been a well- known target to protect the heart from IR injury, but with little success. " ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure. However, our understanding of the regulation of energy metabolism and mitochondrial function in the energy demanding heart remains poor. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1 with unknown function. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits α and β of ATP synthase F1 sector. We were excited to find that ES1 works as an enhancer of ATP production by increasing ATP synthesis and inhibiting ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart subjected to myocardial IR. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in hearts with myocardial IR injury of patients and mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from myocardial IR via its role in facilitating cardiac energy production/reservation. To test this central hypothesis, we will first define the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We will then determine if transgenic and adenoviral-associated virus-mediated ES1 overexpression in the heart protects the heart against myocardial IR injury by its role in regulating energy metabolism. These studies will provide novel insights into how to manipulate energy metabolism to protect the heart from myocardial IR injury. Furthermore, these new fundamental scientific findings will have broader implications in diseases related to other organs and tissues.