HSPA12A对急性心肌梗死的保护作用及机制研究： 对exosome/miR145介导的巨噬细胞“Adam17/MerTK/胞葬功能”信号的正调节

胞葬(Efferocytosis)是指吞噬细胞清除凋亡细胞、产生抗炎因子的过程，而胞葬功能受损是急性心肌梗死(AMI)的关键病理机制。.HSPA12A是功能尚不甚明确的热休克蛋白。前期国家自然基金研究中，我们发现：HSPA12A在AMI心肌细胞中表达减少，而心肌细胞高表达HSPA12A减轻AMI损伤，且该作用可能是通过增加心肌细胞miR145表达、并经exosome到达巨噬细胞、进而激活其MerTK介导的胞葬功能而实现的。.本项目将在前期基础上，采用心肌细胞特异性HSPA12A转基因鼠、基因敲除鼠，综合评价HSPA12A对AMI的保护作用，并结合细胞模型，阐明该作用是否通过心肌细胞exosome负载的miR145来激活巨噬细胞“Adam17/MerTK/胞葬功能”信号活性，快速清除凋亡细胞、抑制炎症反应而实现的。研究结果将从“心肌细胞-巨噬细胞”相互影响的角度，为AMI防治提供基础数据。

Impaired efferocytosis caused accumulation of apoptotic cardiomyocytes and exaggerated inflammation，both of which are critical for myocardial injury of acute myocardial infarction (AMI)..HSPA12A is a novel heat shock protein which biological function is barely known. During the previous NSFC studies, we observed that HSPA12A was downregulated in cardiomyocytes after AMI, and cardiomyocyte-specific overexpression of HSPA12A attenuated AMI-induced cardiac injury. Our preliminary data also suggest that this action of HSPA12A could be mediated by increasing cardiomyocyte-derived exosomes-loaded miR145, which in turn activating macrophage “miR145/MerTK/efferocytosis” signaling system..To test this possibility, we will fully evaluate the protection of HSPA12A against AMI using cardiomyocyte-specific HSPA12A transgenic and knockout mice. We will also investigate whether the protection of cardiomyocyte HSPA12A against AMI is achieved by the activation of macrophage “miR145/MerTK/efferocytosis” signaling using both mice and cell culture models. The results will provide novel clues for identifying potential protective targets of AMI based on the inter-cellular interactions of “cardiomyocyte signaling-macrophage efferocytosis”.