PDK1- Akt信号转导通路与肾素-血管紧张素Ⅱ交互调控改善心梗后心力衰竭的机制研究

The PDK1-Akt signaling and renin-angiotensinII(AngII) signaling is known to collaboratively regulate physiological and pathological cardiomyopathy. However the role of these two signaling pathways is yet to be determined in heart failure after myocardial infarction. Our project is the first to investigate the link between PDK1-Akt and renin-angiotensinII(AngII) signaling in myocardial infarction induced heart failure. In the in vitro culture of hypoxic and wild type(WT) cardiomyocytes, we will observe the modulation of PDK1-Akt signaling on renin-AngII signaling via lentiviral overexpression of Akt or shRNA against Akt. Vise versa we will selectively manipulate renin-AngII signaling to analyze the reciprocal effect Akt signaling. Furthermore, the in vivo mouse model of conditional Akt knock out(KO) in heart will help unveil the function of Akt signaling in the physiopathological development of myocardial infarction induced heart failure. Using the in vitro and in vivo model together, our research will assess the crosstalk between PDK1-Akt and rennin-AngII signaling, and their mechanism in the following key events during the development of myocardial infarction induced heart failure:1. myocardial apoptosis; 2. ventricular remodeling; 3. compromised heart function. We hope that these studies further the understanding of the molecular mechanisms of heart failure and will further the development of more specific targeted therapies for myocardial infarction induced heart failure.

PDK1-Akt信号通路与肾素-血管紧张素Ⅱ(AngⅡ)交互调控理论是心肌生理性与病理性肥大过程中不同信号通路的研究基础上发展起来的，本课题首次将这两条信号通路与心肌梗死后心力衰竭防治结合起来。在体外培养缺氧心肌细胞、野生型和心肌特异性剔除Akt小鼠的动物模型中，通过Akt过表达慢病毒和Akt RNAi 慢病毒调控Akt表达，观察由此对AngⅡ的影响，并以血管紧张素Ⅱ受体拮抗剂干预，了解其对PDK1-Akt信号系统的影响，旨在阐明心肌梗死后PDK1-Akt信号转导通路与肾素-血管紧张素Ⅱ(AngⅡ)交互调控作用机制，以求从相互调控角度研究心脏过度表达Akt在心肌梗死后心力衰竭发展过程中的病理生理作用。同时，比较Akt过表达、血管紧张素Ⅱ受体拮抗剂干预以及两者共同作用分别对心肌梗死模型心肌细胞的凋亡与存活、心室重构和心功能的作用机制，为心肌梗死的药物和基因治疗探索优化组合方案。

PDK1-Akt信号通路与肾素-血管紧张素Ⅱ(AngⅡ)交互调控理论是心肌生理性与病理性肥大过程中不同信号通路的研究基础上发展起来的，本课题首次将这两条信号通路与心肌梗死后心力衰竭防治结合起来。选择两种不同转基因工具鼠，在体外培养缺氧心肌细胞、野生型和心肌特异性剔除Akt小鼠的动物模型中，通过Akt过表达慢病毒和Akt RNAi 慢病毒调控Akt表达，观察由此对AngⅡ的影响，并以血管紧张素Ⅱ受体拮抗剂干预，了解其对PDK1-Akt信号系统的影响，旨在阐明心肌梗死后PDK1-Akt信号转导通路与肾素-血管紧张素Ⅱ(AngⅡ)交互调控作用机制，以求从相互调控角度研究心脏过度表达Akt在心肌梗死后心力衰竭发展过程中的病理生理作用。同时，比较Akt过表达、血管紧张素Ⅱ受体拮抗剂干预以及两者共同作用分别对心肌梗死模型心肌细胞的凋亡与存活、心室重构和心功能的作用机制，为心肌梗死的药物和基因治疗探索优化组合方案。同时发现心肌病变的微环境异常。