HSPA12A打断成纤维细胞“Hif1α-糖酵解-乳酸输出”正反馈环路改善心肌梗死后心肌纤维化的研究

心肌纤维化是心肌梗死(MI)后恶性重塑的关键病理基础，而心肌纤维化依赖于心脏成纤维细胞(CFs)持久活化，但CFs持久活化的机制尚有待阐明。.HSPA12A是HSP70家族成员。在前1项国家自然基金研究中我们发现：(1)缺氧触发的“Hif1α-糖酵解-乳酸输出”正反馈环路，可能介导了CFs持久活化；(2)成纤维细胞HSPA12A减轻MI心肌纤维化，该作用可能是通过增加Smurf1对MCT4泛素化降解、抑制其介导的乳酸输出、打断“Hif1α-糖酵解-乳酸输出”正反馈环路、纠正CFs持久活化而实现的。.本项目将在前期基础上，采用成纤维细胞HSPA12A转基因鼠、基因敲除鼠，综合评价成纤维细胞HSPA12A对MI心肌纤维化的改善作用；并结合细胞模型，阐明“Hif1α-糖酵解-乳酸输出”正反馈环路在CFs活化中的作用，以明确其保护机制。研究结果将从CFs活化的角度，为防治MI心肌纤维化提供新思路。

Cardiac fibrosis is the fundamental pathological event for the development of adverse remodeling post myocardial infarction (MI). The sustained activation of cardiac fibroblasts (CFs) is necessary for cardiac fibrosis. However, it has not been fully understood how CFs is sustained activated post MI. .HSPA12A is a novel member of HSP70 family. During the last NSFC (#81870234) studies, we observed the hypoxia-triggered “Hif1α-glycolysis-lactate export” positive feedback loop was associated with the sustained activation of CFs. More importantly, we found that HSPA12A was downregulated during CFs activation, whereas overexpression of HSPA12A in fibroblasts attenuated post-MI fibrosis. The pilot studies suggest that this action of HSPA12A could be mediated by directly binding to ubiquitin ligase Smurf1 to promote its-mediated MCT4 degradation, thereby inhibits the glycolysis-generated lactate export, which in turn breaks “Hif1α-glycolysis-lactate export” positive feedback loop for the CFs activation..To test this possibility, we will comprehensively evaluate the protection of CFs HSPA12A against post-MI fibrosis using fibroblast-specific HSPA12A transgenic and knockout mice. We will also investigate whether the protection of fibroblast HSPA12A against post-MI fibrosis is achieved by breaking “Hif1α-glycolysis-lactate export” positive feedback loop by using both mice and cell culture models. The results will provide novel clues for identifying potential targets of post-MI fibrosis based on inhibiting CFs activation.