ALDH2对缺血性心肌损伤后心肌代谢重构的影响及机制研究

Heart failure is the end stage of various kinds of heart disease. The incidence of heart failure is high and its prognosis is poor. As interventional therapy progresses, mortality rate of acute cardiovascular incident declines each year. Therefore, post-acute injury phase myocardial preservation is the hotspot of Cardiovascular Research field. Recent research indicated that, metabolic remodeling during heart failure could block the generation of ATP and hinder the conversion from chemical energy to mechanical energy, hence induces irreversible heart failure. Mitochondrial aldehyde dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, was shown to be an important endogenous protector in a variety of cardiac injuries. The deletion genotype of ALDH2 gene is more prevalent in East Asia population. Recently, researchers reported that inactive ALDH2 enzyme enhanced glycolysis and induced metabolic remodeling. However, the influence of ALDH2 on fatty acid and glucose metabolism, the primary energy sources of adult heart, has not been fully elucidated. In this project, we plan to explored the role of ALDH2 deficiency on cardiac energy substrates utilization, fatty acid and glucose utilization and AMPK，PPARa signaling in a murine model, in which left anterior descending(LAD) branch of coronaryartery was ligated to develop ischemic heart failure model. We will study the influence of ALDH2 deficiency onfatty acid metabolism and glucose metabolism, and investigate the molecular mechanisms. Our project will shed light on the prevention and treatment of post-intervention heart failure, especially in the East Asia Chinese population.

心力衰竭是各种器质性心脏病的临床终末阶段，预后凶险。随着介入治疗的推广普及，急性心血管事件死亡率逐年下降，因此度过急性损伤期的心肌保护治疗成为研究热点。一系列研究表明，心衰过程中的代谢重构会导致ATP生成受损，阻碍化学能量向机械能量的转化，最终导致不可逆的心力衰竭。ALDH2是线粒体内的关键酶，是心肌内源性保护因子，东亚人群中ALDH2缺失型分布比西方人群更普遍。最近研究发现ALDH2缺失可促进心肌葡萄糖利用同时导致代谢重构，但是其对脂肪酸及葡萄糖代谢的影响还没有被完全揭示。我们将利用现有的ALDH2-/-小鼠，采用冠状动脉左前降支缩窄术诱导心肌缺血后心衰，然后进行功能学、形态学、能量模式及能量信号通路四个层面的观测。研究ALDH2基因敲除对调控心肌脂肪酸和葡萄糖代谢的作用，探索ALDH2参与心衰发生和发展的分子机制。为东亚特别是中国人群介入后心衰的防治提供实验和理论基础。