AMPK对心肌缺血再灌注损伤中乳酸穿梭系统的作用及机制探讨

Myocardial ischemia-reperfusion injury essentially is an energy metabolism imblance event. Injury of ischemic period due to lack of glycolysis，and injury of reperfusion period caused by insufficient glucose oxidation. We have already confirmed that in the course of myocardial ischemia / reperfusion, the lactate shuttle plays a crucial protective effect. In ischemic period, cardiomyocytes facilitate lactic acid extrusion producesd by glycolysis, while in the reperfusion period lactic acid is taken up by cardiomyocytes as an energy substrate for myocardial contraction. Enhance the expression of lactate shuttle system significantly has much benefits in protecting myocardial ischemia-reperfusion injury. AMPK is the metabolic switch in cells. Related field studies have shown that activation of AMPK pathway may improve the expression of lactate shuttle system in skeletal muscle tissue to increase the exercise tolerance. Heart is also highly oxidative with fast energy supply, and AMPK makes a comprehensive role in myocardial energy metabolism. Thus we make a hypothesis: AMPK may participate in myocardial I/R injury from regulating the lactate shuttle system. The purpose of this study is to explore the role and mechanism of AMPK to lactate shuttle systerm in myocardial I/R injury from the point we noted above, in order to provide a new target for clinical intervention for myocardial ischemia/reperfusion injury.

心肌缺血再灌注损伤（I/R）本质上是一种能量代谢失常事件，即缺血期损伤来自糖酵解不足，而再灌注损伤来自糖氧化不足。我们前期研究证实，在心肌I/R过程中乳酸穿梭有重要的保护作用——缺血期心肌细胞转出乳酸以维持糖酵解继续进行，为心肌存活提供能量；再灌注期心肌细胞外乳酸转入胞内，可作为底物直接氧化供能，维持心肌收缩功能。腺苷酸活化蛋白激酶（AMPK）是细胞内能量开关。最新研究显示，AMPK通路可提高骨骼肌组织乳酸穿梭系统的表达而增加运动耐量，心肌同样具有高度氧化和快速供能特性，AMPK通路也广泛参与心肌能量代谢，由此我们设想:AMPK通路可能对乳酸穿梭系统有调控作用，进而参与心肌I/R的发生发展过程。本研究从AMPK通路及其对乳酸穿梭系统的调控作用入手，探讨该通路对I/R心肌的作用及可能机制，以期为临床防治心肌I/R损伤提供新的靶点。

心肌缺血再灌注损伤本质上是一种能量代谢失衡事件，同时也伴随着氧化还原失衡，两者在心肌缺血损伤中互相影响。缺血时能量不足导致AMPK激活，已有研究证实，缺血引起的氧化应激水平的上升抑制了AMPK的进一步激活。减弱了AMPK的心肌保护作用。我们在对缺血心肌中AMPK对乳酸穿梭蛋白（MCT)作用的研究中发现，AMPK虽能增加MCT的mRNA水平，却未能改变其蛋白水平。我们进一步研究发现乙醛脱氢酶2（ALDH2)通过其抗氧化能力，缓解了氧化应激对AMPK的抑制，并支持AMPK活化的关键蛋白Trx1，促进AMPK的活化的机制。促进ALDH2活性或过表达均可增加AMPK活化及其下游分子PGC-1α水平增加，保护了心肌线粒体功能，抵抗心肌缺血损伤，抑制ALDH2或敲减其水平则加重了心肌损伤。提示在缺血心肌中，通过ALDH2-氧化还原-Trx1/AMPK-PGC-1α将能量代谢失衡和氧化还原失衡两个问题关联，更加有效的保护缺血心肌。这为治疗其他能量代谢失衡和氧化还原失衡共同参与的疾病，如糖尿病，肥胖，癌症等提供了新的思路和理念。