OPA1缺失介导的线粒体自噬水平降低促发慢性心力衰竭及机制

Mortality and morbidity in patients with chronic heart failure (HF) are increasing each year and survival estimates only 50% at 5 years after the diagnosis of HF. So, HF is one of the major causes of human death and disability. Mitochondrial defects reduce the amount of cardiomyocytes energy and relate to many cardiac disorders, which exist in the beginning of hypertrophy and HF. Alteration of mitochondrial function is considered an origin of HF, as well as a target. However, what causes mitochondrial dysfunction in the development of HF has not been fully understood. OPA1 is a dynamic-related protein and mediates the mitochondrial fusion, maintains mitochondrial cristae morphology and prevents mitochondria-related apoptosis. In our latest preliminary study, mice with transverse aortic constriction-induced HF showed decreased mitophagy and OPA1 protein level. On the other hand, deficiency of OPA1 in cardiac-specific OPA1 knockout mice caused mitochondrial dysfunction and HF, meanwhile with lower level of mitophagy. These data suggest that mitophagy possibly plays a role in the development of HF and OPA1 may regulate mitophagy. However, the mechanisms remain largely unknown. Based on these data, we hypothesized that downregulation of mitophagy induced by OPA1 deficiency in cardiomyocytes contributes to development of HF. The present study was designed to clarify this hypothesis and investigate the underlying mechanisms. Proving this hypothesis might gain further insight into the pathogenesis of HF and provide theoretical basis and novel possible targets for preventing mitochondrial dysfunction in HF.

心力衰竭是严重威胁人类健康和寿命的重大慢病，近年国人心衰患病率持续上升，亟需阐明其分子病因学机制以探寻新的防控措施。线粒体自噬是线粒体质控途径的关键环节，然而其在心衰中的变化、作用及上游机制尚未阐明。OPA1是核编码的线粒体蛋白，可介导线粒体融合、防止线粒体途径引发的凋亡等。申请者新近预实验发现，压力负荷性心衰小鼠心肌线粒体自噬水平降低、OPA1蛋白下调，更重要的是，心肌特异性OPA1敲除小鼠线粒体结构功能异常、线粒体自噬水平降低并出现心力衰竭。提示，线粒体自噬水平与心衰进程存在密切联系；OPA1参与线粒体自噬的调控，但其与心衰的关系及机制尚不清楚。本课题拟在前期发现基础上，阐明OPA1下调介导的线粒体自噬水平降低可促发慢性心衰、并进一步研究其机制，期望为深入认识心衰发生的线粒体机理提供实验依据，并为防控心衰提供分子靶点。

心力衰竭（心衰）是冠心病、高血压、糖尿病心肌病等多种心血管疾病的终末阶段，线粒体缺陷可致代谢异常、心肌能量匮乏以及氧化应激增强等，参与心脏的多种病理过程，因此，改善线粒体功能、提高心肌能量供应成为早期防控心血管疾病的可能途径之一。在本项目资助下，我们在国际上首次发现：①压力负荷性心衰小鼠心肌线粒体自噬水平下降，OPA1表达降低；心肌特异性OPA1缺失可诱发小鼠线粒体结构和功能障碍，线粒体自噬水平降低及心力衰竭。OPA1敲除小鼠心肌组织mTOR及下游S6、ULK1磷酸化水平均升高，雷帕霉素腹腔注射可阻断TOR及其下游S6、ULK1磷酸化水平，同时改善OPA1缺失导致的线粒体自噬水平降低、线粒体功能、心肌肥厚和心脏功能下降，OPA1可与ULK1和FUNDC1形成复合体调控线粒体自噬过程，提示其改变是线粒体自噬影响心衰发生发展的关键机制。② 胎球蛋白B（FetB）上调导致胰岛素受体β酪氨酸磷酸化水平降低及其下游信号激活减少，致胰岛素诱导的代谢效应受损和糖尿病缺血心肌损伤加重。③ 长期热水浴可改善慢性应激大鼠心肌自噬紊乱、促进线粒体结构恢复、减轻慢性应激所致的心肌损伤。这些发现不仅对认识心衰发生发展的线粒体相关机理有理论意义，而且对探索新的防治措施有现实意义。