PDHc对心脏缺血性损伤中AMPK通路的影响

PDHc, a multi-enzyme complex located in the mitochondrial matrix, plays a key role in aerobic energy metabolism. This multienzyme complex occupies a central crossroad of glycolysis, and the tricarboxylic acid cycle by catalyzing the oxidative decarboxylation of pyruvate to form acetyl CoA. There is altered cardiac glucose in various pathophysiological states consequently causing PDHc to be altered. We have revealed that AMP-activated protein kinase (AMPK) signaling is an important contributing factor leading to increased sensitivity to ischemic stress. Glucose metabolism is regulated by PDH via altering its activity under ischemic stress. Therefore, it is hypothesized that the impaired PDH-AMPK signaling cascade contributes to intolerance to ischemic insults. We will test this hypothesis to investigate the importance of PDHin the susceptibility to ischemic insults.Aim 1: To determine the role of PDH in regulating cardiac function during ischemia stress; Aim 3: To determine the regulation between PDH and AMPK and the mechenism of the regulation. In this manner, we will advance our understanding of the role of PDH in regulating metabolism under myocardial infarction. This grant seeks to understand the ways in which impaired cardioprotective signaling leads to a higher incidence of ischemic heart disease, and has the potential to discover new therapeutic strategies to limit myocardial dysfunction.

丙酮酸脱氢酶复合体（PDHc）是线粒体基质内的多酶复合物。通过催化丙酮酸不可逆地氧化脱羧成乙酰辅酶A，连接糖酵解作用，柠檬酸循环以及ATP形成。已有证据显示心脏在不同病理条件下，PDH活性随之改变，进一步影响心脏中葡萄糖的代谢。我们前期工作证实AMP激活的蛋白激酶（AMPK）在缺血状态下调解能量代谢，而心脏特异性敲除PDH，会加重缺血损伤，并影响AMPK活性。本课题以野生型及PDH基因敲除小鼠为研究对象，研究① PDH活性调节在心肌缺血中所起的作用，②心脏在缺血状态下，PDH对AMPK的调节，③ PDH 是如何调控AMPK影响心脏对缺血性损伤的抵御能力的。从而阐明PDH在心肌缺血所致的心脏损伤中的重要作用。

缺血性心肌病（IHD）是指由于冠状动脉狭窄闭塞，以及心肌慢性缺血引起的心肌供血、供氧障碍，导致心肌收缩舒张功能受损以及心肌梗死。由于心肌的高耗能特性，IHD也可称为“代谢疾病”。在心肌梗死过程中，心脏需要快速适应缺氧/缺血状态，经历从有氧代谢到无氧代谢的巨大转变。缺血状态下心肌能量代谢的适应性改变对缺血心肌的能量维持和抗缺血能力至关重要。因此，阐明心肌缺血过程中调控能量代谢的关键因子并探寻相应的IHD防治策略是亟待解决的重要问题。研究目的① 明确PDH活性对心肌缺血损伤的影响；②明确心肌缺血状态下，PDH对心肌葡萄糖代谢的调节作用，③ 探讨PDH上述生物学作用是否与AMPK有关并分析PDH与AMPK相互作用的分子机制。本研究首次采用诱导型心肌特异性PDH E1α敲除小鼠证实PDH是维持心肌心肌能量代谢以及收缩舒张功能的关键因子，激活PDH可以有效调整缺血心肌的底物代谢。我们首次发现，心肌PDH与AMPK存在直接调控关系，PDH缺失可导致AMPK失活并显著加重心肌缺血损伤。