Drp1依赖性的线粒体自噬在慢性间歇性缺氧致心肌重构中的作用机制研究

OSAS can induces multiple cardiovascular complications, cardiac remodeling is one of the most common complications of them. Mitochondrial autophagy is considered to be an important mechanism to maintain cardiomyocyte homeostasis and has been proved to be related closely to the myocardial remodeling caused by multiply pathological factors, such as aging, hypoxia, ischemia-reperfusion. Present researches have proved that CIH can induce myocardiac remodeling, but whether mitophagy was involved in this pathological process or not and the exactly mechanism are still unrevealed. In our present study, we employ animal and cell modes exposed to CIH as well as human studies to investigate the effects of cardiomyocyte mitophagy in the process of cardiac remodeling induced by chronic intermittent hypoxia. Furthermore, we specially blocked the signal transduction of the Drp1/mitophagy signaling pathway by using chemical blockers including key signaling molecules, or via genetic tools (gene knockout，RNA interference, RNAi) to understand the specific role and mechanism in order to yield a greater understanding regarding the molecular mechanism undrtling OSAS-induced cardiac remodeling and suggest novel treatment options for this condition.

阻塞性睡眠呼吸暂停综合征（OSAS）可以引起多种心血管系统的并发症，心肌重构是其中最常见的并发症之一。线粒体自噬（mitochondrial autophagy）被认为是一种重要的维持心肌细胞内环境稳态和正常功能的生理机制，已被证实与老龄化、缺氧、缺血再灌注等多种病理情况所引发的心肌重构关系密切。本研究组的前期研究也证实慢性间歇性缺氧（CIH）可以导致心肌重构的发生，但线粒体自噬机制是否参与到了该类型心肌重构的发生过程中，且其机制又如何尚不明确。本研究拟通过暴露于慢性间歇性缺氧环境的动物以及细胞模型，结合人体的研究来探讨慢性间歇性缺氧造成心肌重构的情况。同时，我们还将通过上调线粒体自噬的水平来探讨线粒体自噬在CIH造成的心肌重构中的作用。同时还利用Drp1/Mitophagy信号通路中关键信号的化学阻滞剂或者基因手段（基因敲除, RNA 干扰技术, RNAi）来阻断该通路的各个环节

阻塞性睡眠呼吸暂停综合征（Obstructive sleep apnea syndrome,OSAS）是一种全身性疾病，特征性表现为间歇性缺氧(intermittent hypoxia,IH)，可导致心肌肥厚，最终导致心衰甚至死亡，但其作用机制尚不十分明确。本研究探讨胰腺beta细胞团的关键调控因子(Fork Head Box Class O1,FOXO1)抑制剂AS1842856 缓解IH诱导心肌细胞凋亡及心肌肥厚的潜在分子机制,为AS1842856治疗OSAS心肌肥厚并发症提供理论基础。研究表明FOXO1/Bim信号通路调节了IH 诱导的心肌细胞凋亡。IH 诱导了大鼠心肌细胞凋亡及心肌肥厚，FOXO1/Bim信号通路调节了IH诱导的心肌细胞凋亡，AS1842856缓解了IH 诱导的心肌细胞凋亡及心肌肥厚。