心肌保护因子CTRP9在阻塞性睡眠呼吸暂停加重缺血性心肌损伤中的保护作用及机制研究

阻塞性睡眠呼吸暂停（OSA）是多种心血管疾病的共同危险因素，但分子机制不明，有效干预靶点匮乏。申请者前期原创性发现，OSA减低新型心脏保护因子CTRP9水平，加重缺血性心肌损伤。离体细胞预实验进一步发现，CTRP9球状片段（gCTRP9）而非全长CTRP9是其发挥心脏保护作用的直接分子。但心脏CTRP9的细胞表达谱、CTRP9蛋白酶切谱及心肌保护的受体通路均不明了。本项目结合细胞研究阐明机制与在体疾病模型验证效应的研究模式，综合基因干预与分子生物学技术，确定心肌细胞与心脏成纤维细胞在心脏CTRP9基因表达与CTRP9蛋白酶切激活中的作用，揭示gCTRP9保护心肌的受体与细胞内通路，阐明OSA对这些关键环节的影响及机制，验证OSA通过抑制CTRP9转录表达与翻译后酶切激活等多种机制加重心脏缺血性损伤的科学假设，为寻求以CTRP9为切入点而有效保护OSA合并缺血性心肌损伤的新策略提供实验依据。

Obstructive sleep apnea (OSA) is a common risk factor for many cardiovascular diseases, but the molecular mechanism is unknown, and there is a lack of effective intervention targets. Our previous original results showed that OSA reduced the level of cardioprotective cardiokine CTRP9 and aggravated ischemic myocardial injury. In vitro preliminary data revealed that globular CTRP9 fragment (gCTRP9) instead of full-length CTRP9 serves as a direct molecule for its cardioprotective effect. However, the specific cellular type(s) responsible for cardiac CTRP9 production, the molecular mechanisms responsible for cardiac CTRP9 cleavage, and the receptor pathway of myocardial protection are unknown. This study will utilize gene intervention combined with molecular techniques to determine the role of cardiomyocytes and cardiac fibroblasts in CTRP9 gene expression and CTRP9 proteolytic activation, reveal the receptors and intracellular pathways of gCTRP9 protected myocardium, clarify the effect and mechanism of OSA on these key links, and validate the scientific hypothesis that OSA exacerbates ischemic myocardial injury by inhibiting CTRP9 transcription expression and post-translational enzyme activation. This study will provide experimental basis for seeking a new strategy that uses CTRP9 as an entry point to effectively protect OSA with ischemic myocardial injury.