ACE2-Ang-(1-7)-Mas轴对压力超负荷诱导心肌细胞自噬的作用及机制

Autophagy is a compensatory response for cardiac injury as well as a form of programmed cell death. Recent evidence from our laboratory revealed that cardiac autophagy was significantly increased in pressure overload-induced cardiac remodeling, which indicated that cardiac autophagy may play an important role in the mechanism of cardiac remodeling. The ACE-AngⅡ-AT1 axis is an important player in cardiomyocyte autophagy and cardiac remodeling.However,the role of ACE2-Ang(1-7)-Mas axis played in cardiomyocyte autophagy is still not known.We hypothesize that ACE2-Ang(1-7)-Mas axis will inhibit pressure overload-induced excessive autophagy. This study is designed to construct pressure overload model in vivo and in vitro,and we will examine the role of the ACE-AngⅡ-AT1 axis and ACE2-Ang(1-7)-Mas axis in the influence cardiomyocyte autophagy. In parallel, the probable signal pathways involved in it, including MAPK and Akt will be investigated by using drugs and genetic intervention. The results will provide experimental evidences for the effect of ACE2/Ang-(1-7)/Mas axis on the treatment of pressure overload-induced heart failure. This study will also shed some lights towards the therapeutic promises of autophagy regulators in pressure overload-induced heart failure.

自噬是心肌对损伤的代偿性反应，也是细胞程序性死亡方式之一。我们前期研究显示：在压力超负荷引起心肌重构中，心肌细胞自噬显著增多，提示过度的自噬可能是心肌重构的重要原因。血管紧张素(Ang)系统中，AngⅡ通过AT1受体参与心肌细胞自噬和心肌重构，而ACE2-Ang-(1-7)-Mas轴对心肌重构有保护作用，但其是否调控心肌细胞自噬尚不清楚。我们推测ACE2-Ang(1-7)-Mas轴负向调控心肌细胞自噬。本课题将采用体外机械牵张和在体主动脉缩窄方法制作小鼠心肌细胞和心脏压力超负荷模型，通过药理和基因等干预手段，研究ACE-AngⅡ-AT1轴和ACE2-Ang(1-7)-Mas轴在心肌细胞自噬中的关系及其对心肌重构和心功能的影响，并探讨MAP激酶,AKT激酶信号通路蛋白的作用，从而阐明压力超负荷诱导心肌细胞自噬发生发展的分子机制，完善对心肌重构和心力衰竭机制的认识，为寻找新的干预靶点提供参考。

自噬是心肌对损伤的代偿性反应，也是细胞程序性死亡方式之一。过度的自噬参与了压力超负荷诱导的心肌重构及心力衰竭。我们的研究显示：在压力超负荷引起心肌重构中，心肌细胞自噬显著增多， AT1受体参与了心肌细胞自噬和心肌重构。ACE2-Ang-(1-7)-Mas受体轴是RAS的一个新分支，它与AT1受体的多种生物学作用相拮抗。然而，ACE2-Ang-(1-7)-Mas是否调控心肌细胞自噬尚不清楚。我们从在体、离体两方面证实压力超负荷显著引起心肌细胞自噬蛋白LC3b-II增多。此外，压力超负荷引起MDA增多、SOD减少，说明压力超负荷诱导氧化应激。Ang-(1-7)显著抑制心肌细胞自噬、氧化应激、减轻心肌重塑。给予Mas受体阻断剂A779逆转了Ang-(1-7)的保护作用如减少心肌细胞自噬、氧化应激和减轻心肌重塑。以上结果说明：Ang-(1-7)通过Mas受体抑制压力超负荷诱导的心肌细胞自噬和心肌重塑。Ang-(1-7)有望成为一个抑制压力超负荷诱导的心肌细胞自噬和心肌重塑的的新药物。