GPR48调控心脏细胞命运转变和炎症级联反应参与心梗后心脏重构的作用和机制研究

巨噬细胞炎症参与心梗后心肌损伤和重构。我们研究发现：1）G蛋白偶联受体-GPR48激活突变与早发心梗和心功能恶化相关；2）GPR48主要表达于巨噬细胞，可能通过PKA-CREB调控S100a8/S100a9表达，参与心梗后心脏重构；3）S100a8/S100a9通过结合模式识别受体TLR4/RAGE介导NLRP3炎症小体活化和细胞焦亡等。据此提出假设：急性心梗激活心脏巨噬细胞GPR48，通过PKA-CREB通路促进S100a8/S100a9表达释放，结合TLR4/RAGE自我诱导M1巨噬细胞活化，同时激活心肌细胞和成纤维细胞发生命运转变-细胞焦亡和炎症级联反应，参与心梗后心肌损伤和重构。为此，本课题将利用骨髓移植嵌合技术、多种细胞特异性基因敲除小鼠、GPR48阻断抗体和临床样本等明确GPR48参与心梗后心脏重构的功能作用和分子免疫机制。为防治心脏重构和心衰提供新的治疗策略和干预靶点。

Macrophage inflammation is involved in myocardial injury and remodeling after myocardial infarction. Our previous studies have shown that: 1) By using the exome sequencing, GPR48 active mutation (rs149204548) is independently associated with premature myocardial infarction (MI) and cardiac dysfunction after MI; 2) GPR48, mainly expressed on macrophages, contributes to cardiac ischemic injury and post-MI remodeling via regulating S100a8/S100a9 expression through PKA-CREB pathway; 3) Previous studies demonstrated that S100A8/S100A9 promotes NLRP3 inflammasome activation and pyroptosis through binding of pattern recognition receptors (PRRs)-TLR4/RAGE. Thus, based on these findings, we proposed that myocardial infarction activates GPR48 and secretion of S100a8/S100a9 through PKA-CREB signaling pathway, and S100a8/S100a9 induces M1 macrophage differentiation, cardiomyocyte and fibroblast pyroptosis and Inflammatory cascade，contributing to the development of cardiac remodeling after myocardial infarction. To this end, the present study will apply bone marrow transplantation, multiple tissue specific knockout mice and blocking antibody for GPR48 to explore the functional role of GPR48 and its underlying mechanism. We also try to elucidate the relationship between GPR48-S100a8/S100a9-IL-1β expression in circulating monocytes and severity of myocardial infarction. Our findings will provide provide new therapeutic targets for prevention of cardiac remodeling and heart failure.