衰老小鼠心肌中过表达的促凋亡蛋白Omi/HtrA2通过线粒体自噬致老年心力储备降低的机制研究

随年龄增加而出现的心力储备降低严重影响老年人的生活质量，研究认为心肌细胞凋亡的增加是致老年心力储备降低的重要原因。我们原创性的研究发现，衰老心肌中线粒体促凋亡蛋白Omi/HtrA2的过表达参与了老年心力储备降低，但机制不清。本研究拟通过心脏注射Omi/HtrA2的特异性抑制剂UCF-101及线粒体激活剂/抑制剂、质粒过表达/RNA干扰等技术，观察自噬水平、心肌细胞凋亡和心力储备的改变，证实衰老心肌中Omi/HtrA2的过表达通过PINK1-parkin-Mfn2途径和/或Drp1非依赖Parkin途径下调线粒体自噬，降低心力储备，其中转录因子HSF1是促进衰老心肌Omi/HtrA2表达的主要原因。本研究将为把Omi/HtrA2作为一个潜在的改善老年心脏心力储备的靶点提供了实验依据。

The decreasing of cardiac reserve reduced the life quality of the elderly with aging. It is reported that cardiomyocyte apoptosis are responsible for lower cardiac reserve in aging heart. Our previous study found that the overexpression of a mitochondrial pro-apoptosis protein Omi/HtrA2 was participated in cardiac reserve in aging heart. However, its mechanism is unclear. In this study, we will observe the cardiac reserve, apoptosis, mitophagy after injection UCF – 101(specific Omi/HtrA2 inhibitor), mitophagy activator /inhibitors in heart, and plasmid transfection /RNA interference technology in H9c2, to prove that overexpression of a pro-apoptosis protein Omi/HtrA2 decrease cardiac reserve through PINK1-parkin-Mfn2 pathway and/or Drp1 parkin-independent pathway mitophagy, and HSF1 is the main cause of overexpression of Omi/HtrA2 in aging heart. It will provide the evidence for Omi/HtrA2 to become a potential target to improve the cardiac reserve in aging heart.