血管内皮生长因子促进线粒体细胞色素C氧化酶活性的分子机制

Cytochrome c oxidase (CCO), the terminal enzyme of mitochondrial respiratory chain, determines the function of mitochondrial and ATP synthesis and plays the key role in maintaining cardiomyocyte structure and function. Our previous studies have shown that VEGF restore phenylephrine (PE) induced CCO activity decrease. Further studies have shown that PE treatment increased both intracellular and extracellular concentrations of homocysteine, which was found to form complexes with Cu in vitro. Inhibition of the intracellular homocysteine synthesis in the PE-treated cardiomyocytes prevented the increase in the extracellular homocysteine concentration, retained the intracellular Cu concentration, and preserved the CCO activity. PE treatment decreased protein concentrations of a CCO subunit COX-IV, and Cu chaperones for CCO, including COX17, COX11, and SCO2. These PE effects were prevented by either inhibition of the intracellular homocysteine synthesis or Cu supplementation. Therefore, PE-induced elevation of homocysteine restricts Cu availability through its interaction with Cu and suppresses the expression of Cu chaperones, leading to the decrease in CCO enzyme activity. In this project, we will test the hypothesis that VEGF restore CCO activity by inhibiting intracellular homocysteine concentration. The results will provide new understanding for myocardial tissue injury and repair

细胞色素C氧化酶是线粒体氧化呼吸链的终末端酶，决定着线粒体的功能和ATP的合成，其活性对心肌细胞结构正常、功能正常发挥起着至关重要的作用。我们的前期研究结果发现，在去氧肾上腺素诱导的大鼠心肌细胞肥大模型中，血管内皮生长因子可以逆转去氧肾上腺素诱导的细胞色素C氧化酶活性下降。进一步的研究发现，去氧肾上腺素通过增高细胞内同型半胱氨酸含量，引起细胞内铜含量下降。因为铜是细胞色素C氧化酶的组成与活性的必须元素，因此铜的缺乏抑制细胞色素C氧化酶的活性；添加抑制剂抑制细胞内同型半胱氨酸的产生，可抑制细胞内铜含量的下降，从而抑制去氧肾上腺素诱导的细胞色素C氧化酶活性下降。因此在本项目中我们将利用去氧肾上腺素诱导的大鼠心肌细胞肥大模型，深入探索血管内皮生长因子是否通过抑制细胞内同型半胱氨酸含量，促进细胞色素C氧化酶活性恢复并阐明相关分子机制。本研究结果将为心肌组织损伤与修复提供新的认识。