G0S2调节线粒体氧化应激干预心肌肥厚重构过程的机制研究

The involvement of mitochondrial reactive oxygen species (m-ROS) in the progression of pathophysiologies of cardiac hypertrophy has been recognised, however, the role and mechanisms of G0S2 mediating m-ROS generation in regulating cardiac hypertrophy has never been reported. Our preliminary data have shown that pressure overload induced the increase of m-ROS generation in heart. Furthermore, over-expression of G0S2 enhanced mitochondrial F0F1-ATP synthase and repressed m-ROS generation. Since m-ROS has been nicely shown to induce cardiac hypertrophy, we hypothesize that G0S2 mediates m-ROS generation contributing to the pathophysiological progress of cardiac hypertrophy. Accordingly, the present project is proposed to investigate the role of G0S2 in cardiac hypertrophy and to explore the underlying mechanisms. Specially, we will induce cardiac hypertrophy by pressure overload on cardiac mitochondrial specific G0S2mito over-exprssion mice and study how G0S2 mediates m-ROS generation leading to cardiac hypertrophy. In cultured cardiomyocytes, we will confirm the in vivo findings. The completion of present study will help understand the molecular mechanisms by which G0S2 mediates m-ROS generation and provide novel therapeutic targets for new drug design to treat the cardiac hypertrophy.

线粒体活性氧（m-ROS）生成参与心肌肥厚的病理生理过程，然而在心肌肥厚过程中G0S2调控m-ROS的的机制研究却未见报道。我们的前期研究已证实F0F1-ATP synthase/m-ROS生成路径是心肌肥厚发生的重要机制，预实验中G0S2过表达能够上调线粒体F0F1-ATP synthase的表达并抑制m-ROS生成，据此推测调控m-ROS生成是G0S2参与心肌肥厚过程的可能机制之一。本课题拟利用心肌细胞线粒体特异性G0S2过表达小鼠构建压力超负荷型心肌肥厚模型，观察G0S2对m-ROS的调控作用，进一步在细胞水平揭示G0S2通过调节F0F1-ATP synthase进而干预m-ROS生成的分子机制及信号通路。本课题通过阐明G0S2与m-ROS生成的关系，以拓展对心肌肥厚发生发展的分子调控机制的认识，为有效干预和治疗心肌肥厚的药物研发提供新的思路。

线粒体活性氧（m-ROS）生成参与心肌肥厚的病理生理过程，然而在心肌肥厚过程中G0S2调控m-ROS的的机制研究却未见报道。我们的前期研究已证实F0F1-ATP synthase/m-ROS生成路径是心肌肥厚发生的重要机制，预实验结果提示G0S2过表达能够上调线粒体F0F1-ATP synthase的表达并抑制m-ROS生成，据此推测调控m-ROS生成是G0S2参与心肌肥厚过程的可能机制。课题以此为基础，利用心肌细胞线粒体特异性G0S2过表达小鼠构建压力超负荷型心肌肥厚模型，观察G0S2对m-ROS的调控作用，进一步在细胞水平揭示G0S2通过调节F0F1-ATP synthase进而干预m-ROS生成的分子机制及信号通路。本课题通过阐明G0S2与m-ROS生成的关系，以拓展对心肌肥厚发生发展的分子调控机制的认识，为有效干预和治疗心肌肥厚的药物研发提供新的思路。另外，我们探讨了Nogo-B对小鼠血管平滑肌细胞中线粒体活性氧生成和血管重构的影响，血管重构过程中血管平滑肌细胞内的m-ROS生成、纤维化指标及线粒体功能受损增加，而过表达Nogo-B可减少m-ROS生成、纤维化指标及线粒体功能受损，明确Nogo-B通过调节ATP合酶进而干预m-ROS生成的分子机制。因此，研究证实Nogo-B通过调节ATP合酶介导m-ROS生成进而参与血管氧化应激损伤以及血管重构过程。