AMPK对活性氧族的调节在β-肾上腺素受体介导心脏重塑中的保护作用

Heart failure is characterized by enhanced sympathetic nervous activity and subsequent activation of beta-adrenergic receptors (bAR) through release of stress hormones (catecholamines). Reactive oxygen species (ROS) induced by bAR activation plays important role in the development of heart failure. Recent years, the cardioprotective effects of AMP-activated protein kinase (AMPK) have caused concern. In our previous study, AMPK agonists attenuate the increase of myocardial ROS and cardiac remodeling induced by bAR, but the mechanism is still unclear. In the present study, we hypothesized that the decrease of AMPK activity is the key mechanism for the increase of ROS induced by bAR activation and AMPK attenuates cardiac remodeling through regulation of ROS. We aim to delineate the role of AMPK pathway in cardiac oxidative stress and remodeling. This study would provide important insights on the mechanisms by which AMPK activation contributes to the inhibition of cardiac remodeling, and experimental evidence for the design of better therapeutic strategy for heart failure.

慢性心力衰竭是一种严重危害人类健康的疾病，交感兴奋/β-肾上腺素受体（β-AR）激活后导致心肌活性氧族（ROS）增多是心脏重塑和心力衰竭发生发展的关键因素。因此深入研究β-AR激动引起心脏ROS增多的机制，可能是心脏重塑防治的重要策略。近年来，"能量代谢感受器"腺苷酸-活化蛋白激酶（AMPK）的心脏保护作用引起关注。我们前期研究表明AMPK 激动剂减轻β-AR激动引起的心肌ROS增多和心肌重塑，但分子机制尚不清楚。本研究提出AMPK 活性降低是β-AR引起活性氧族增多的重要机制，而激活AMPK通过对心脏活性氧族的调节发挥抑制心脏重塑作用的假说。本项目拟阐明AMPK 信号通路在β-AR激动引起活性氧族增多中的重要作用；揭示β-AR调控AMPK的分子机制和激活AMPK 抑制心脏氧化应激和心脏重塑的分子机制；为心脏重塑的抗氧化治疗提供新的思路，为优化心力衰竭的治疗策略进行初步实验探索。

慢性心力衰竭是一种严重危害人类健康的疾病，交感兴奋/β-肾上腺素受体（β-AR）激活后导致心肌活性氧族（ROS）增多是心脏重塑和心力衰竭发生发展的关键因素。因此深入研究β-AR 激动引起心脏ROS 增多的机制，可能是心脏重塑防治的重要策略。我们在本研究中，发现AMPK活性降低是β-AR 引起活性氧族增多的重要机制，而激活AMPK通过对心脏活性氧族的调节发挥抑制心脏重塑作用，本项目阐明AMPK 信号通路在β-AR 激动引起活性氧族增多中的重要作用；研究了激活AMPK 抑制心脏氧化应激和心脏重塑的分子机制，发现AMPK激活后通过调节NADPH氧化酶的活性，使得心脏产生氧自由基减少，通过增加SOD，CAT等酶增加心脏清除氧自由基的能力，为心脏重塑的抗氧化治疗提供新的思路，为优化心力衰竭的治疗策略进行初步实验探索。