OSM/IP7信号通路在糖尿病合并心脏缺血再灌注损伤线粒体质量控制中的作用

Eighty percent of death in diabetic patients was caused by cardiovascular disease. It is our cardiologists’ urgent obligation to reduce the cardiac mortality of diabetic patients. Our research team constructed cardiac ischemia-reperfusion (I/R) injury model by diabetic mice and found that oncostatin M (OSM) pretreatment reduced inositol pyrophosphate 7 (IP7) expression. The mechanism was associated with improved mitochondrial biogenesis and mitochondrial function. Mitochondrial quality control is a vital mechanism to maintain the structure and function of mitochondria. However, it is unclear whether the OSM/IP7 signaling protect against cardiac I/R injury in diabetic mice by modulating mitochondrial quality control. OSM transgenic mice, OSM knockout mice and OSM receptor Oβ knockout mice will be used to construct diabetic models with cardiac I/R injury. The role of mitochondrial quality control and the molecular mechanism of OSM in protecting against cardiac I/R injury in diabetic mice will be investigated. The present project will help enrich the molecular mechanisms of diabetes aggravating cardiac I/R injury and provide new targets to reduce the cardiac mortality of diabetic patients.

80%的糖尿病患者死于心血管疾病，降低糖尿病患者的心源性死亡率，是心血管医师急需攻克的难题。本课题组前期研究发现，抑瘤素M（OSM）预处理降低心肌组织7磷酸肌醇（IP7）表达，减轻糖尿病状态下的心脏缺血/再灌注（I/R）损伤，其机制可能与改善线粒体生物合成及线粒体功能相关。线粒体质量控制是维持线粒体结构完整及功能正常的重要机制，OSM/IP7信号通路是否通过调控线粒体质量控制降低糖尿病状态下的心脏I/R损伤，目前尚不清楚。本课题组针对以上问题，以OSM转基因及基因敲除鼠，OSM受体Oβ基因敲除小鼠为研究对象，构建糖尿病及心脏缺血再灌注损伤模型，揭示OSM/IP7信号通路在上述病理状态下，调控线粒体质量控制的作用及分子机制。本项目的成功实施可丰富糖尿病加剧心脏缺血再灌注损伤的理论基础，为降低糖尿病患者的心源性死亡率提供理论指导和新的思路。

80%的糖尿病患者死于心血管疾病，降低糖尿病患者的心源性死亡率，是心血管医师急需攻克的难题。本研究发现（1）糖尿病状态下，Mst1磷酸化上调并促进IP7生成，导致心肌细胞中大量损伤线粒体聚集，线粒体嵴断裂和空泡化显著，线粒体质量控制异常。OSM抑制Mst1磷酸化，抑制IP7生成，改善糖尿病状态下心肌细胞胰岛素敏感性、抑制凋亡并改善线粒体功能，以“一药三靶”的方式，降低糖尿病状态下心肌缺血再灌注损伤。（2）抑制Mst1磷酸化可促进Parkin向线粒体募集活化，招募p62标记受损线粒体，通过与自噬小体双层膜结构形成关键蛋白LC3-Ⅱ结合，实现对损伤线粒体的特异性清除，维持糖尿病状态下线粒体质量控制稳态。（3）建立Mst1，Sirt3，Parkin转基因及基因敲除动物糖尿病心肌病模型，发现 Mst1敲除可通过抑制Sirt3及Parkin介导的线粒体自噬，实现糖尿病心肌病线粒体质量控制的“靶向保护”。（4）发现糖尿病状态下线粒体形态动力学控制（线粒体分裂/融合）紊乱。抑制Mst1/CDK1-cyclinB/Drp1信号通路，激活Drp1 Ser616位点去磷酸化，促进线粒体膜上的Drp1与MFF及Mid49/51解聚，抑制胞内Drp1向线粒体募集，可维持线粒体分裂融合动态平衡。本研究揭示了OSM/Mst1/IP7信号通路调控线粒体质量控制紊乱，是糖尿病合并心肌缺血再灌注损伤的关键干预靶点。