NADPH氧化酶1在心肌梗死后心力衰竭中的作用及其机制

NADPH oxidase (Nox) is a major source of reactive oxygen species (ROS). Nox activity is increased after myocardial infarction (MI). Nox1 mediates endotoxin-induced cardiac myocyte apoptosis. However, the role of Nox1 in ventricular remodeling and heart failure after MI remains unclear. Nerve growth factor (NGF) plays an important role in the growth, development, differentiation and regeneration of neurons. Recent studies have demonstrated the prosurvival activity of NGF on cardiac myocytes. We have shown previously that NGF is expressed in cardiac myocytes and reduced in cardiac myocytes in heart failure. However, whether reduced NGF in cardiac myocytes is associated with increased ROS in heart failure remains to be elucidated. It is not known that whether Nox1-derived ROS mediate the reduction of NGF in cardiac myocytes, resulting in myocardial remodeling. In this proposal, we will use Nox1 knockout mice and rat ventricular myocytes in culture to test the novel hypothesis that Nox1-derived ROS mediate the reduction of NGF that results in cardiac myocyte apoptosis, leading to ventricular remodeling and heart failure after MI. The proposed study will elucidate the role of Nox1-derived ROS in mediating myocardial remodeling after MI and the underlying mechanisms at the whole body, cellular and molecular levels and provide the novel theory and targets for the prevention and treatment of myocardial remodeling and heart failure after MI.

NADPH氧化酶（Nox）是活性氧（ROS）的主要来源之一。心肌梗死（MI）后Nox活性增加。Nox1介导内毒素诱导的心肌细胞凋亡。 然而，Nox1在MI后心室重构和心衰中的作用不清楚。神经生长因子（NGF）对神经元的生长，发育，分化和再生起重要作用。近年发现NGF可促进心肌细胞存活。我们前期研究表明NGF在心肌细胞中表达，心衰时心肌细胞NGF表达降低。然而，NGF的降低是否与ROS增加有关不清楚。Nox1源性ROS是否介导心衰时NGF的下调，促进心肌重构目前一无所知。本研究将采用Nox1基因敲除小鼠和大鼠心室肌细胞培养模型，验证这个新的科学假设：Nox1源性ROS介导MI后心肌细胞NGF的下调，进而导致心肌细胞凋亡，促进心室重构和心衰。本课题拟从整体，细胞和分子水平研究，将阐明Nox1源性ROS在梗死后心室重构中的作用及其机制，为梗死后心肌重构和心力衰竭的防治提供新的理论依据和靶点。

NADPH氧化酶是活性氧（ROS）的主要来源之一。Nox1是NADPH氧化酶主要亚单位。然而，Nox1在MI后心室重构和心衰中的作用不清楚。近年发现神经生长因子（NGF）可促进心肌细胞存活。我们前期研究表明，心衰时心肌细胞NGF表达降低。然而，NGF的降低是否与ROS增加有关不清楚。Nox1源性ROS是否介导心衰时NGF的下调，促进心肌重构目前一无所知。本研究首先采用NADPH氧化酶亚单位Nox1基因敲除小鼠，探究是否NADPH氧化酶源性ROS介导心肌梗死（MI）后心衰时心肌NGF下调，心肌重构和心功能不全。结果表明, Nox1 基因敲除可减小心肌梗死面积，减轻MI所致心肌NGF下调，心肌纤维化，左室重构，心功能不全和心力衰竭。提示Nox1 NADPH氧化酶源性ROS介导MI后心力衰竭时心肌NGF下调，心肌重构和心功能不全。. 第二，在MI诱导心衰动物模型上，观察是否NADPH氧化酶抑制剂（Apocynin）或具有超氧歧化酶和过氧化氢酶双功能化合物（EUK134）减轻氧化应激，抑制NGF下调，减少心肌细胞凋亡，改善左心室重构和心功能。结果表明，Apocynin或EUK134可预防MI后心肌NGF降低，进而减轻心肌细胞凋亡，改善心肌重构和心功能。此外，NADPH氧化酶抑制剂可减轻MI诱导心衰时心脏交感神经末梢密度减少和功能的降低。提示通过抑制NADPH氧化酶源性氧化应激，预防心衰时心肌NGF降低，减轻心脏交感神经末梢密度减少， 改善心肌重构和心功能。. 第三，在离体大鼠心肌细胞培养模型和小鼠MI诱导心衰模型上，观察是否NGF干预治疗能减少心肌细胞凋亡，减轻左心室重构和改善心功能。结果表明，NGF干预可减轻模拟缺血所致NGF降低和心肌细胞凋亡；NGF干预治疗可减轻MI诱导心肌重构和心功能的降低。 . 此外，在阿霉素诱导心衰模型上，NADPH氧化酶2抑制剂GSK2795039通过抑制氧化应激，预防RIP1-RIP3-MLKL介导的程序性心肌细胞坏死，进而改善心肌重构和心功能。 . 上述研究结果提示,NADPH氧化酶抑制剂或抗氧化剂，通过降低心肌氧化应激，减轻NGF下调，改善心脏交感神经末梢密度和功能，减少心肌细胞凋亡，抑制心肌细胞程序性坏死，进而改善心肌重构和心力衰竭。这些研究成果具有广泛的应用前景。