钙敏感受体通过NLRP3炎症体活化参与T细胞介导心室重塑的研究

Ventricular remodeling is the fundamental mechanism and leading cause of heart failure after myocardial infarction. How to prevent or reverse the development of ventricular remodeling has been an important issue.Recent evidence suggests that the infiltration of T cells and release of cytokines are involved in the process of acute myocardial infarction (AMI). However, the mechanisms are still under investigation.We found for the first time the infiltration of CD4+T cells and the upregulation of calcium-sensing receptor (CaSR)，along with the activation of NLRP3 inflammasome which could induce myocardial fibrosis in CD4+ T cells of rats with AMI.Therefore，it is tempting to speculate that the activation of CaSR in CD4+T cell during AMI, could induce NLRP3 inflammasome activation.This process will result in the release of cytokines,such asIL-1β, from CD4+ T cells and subsequently leads to the myocardial fibrosis and ventricular remodeling via their receptors of fibroblast.In order to clarify the effect and mechanism of CaSR in T cell-mediated immunity during ventricular remodeling, we will study the regulation of CaSR expression, NLRP3 inflammation activation, release of inflammatory factors and related cell signaling pathway in AMI patients, rat model and cell co-culture model. Our research will give new insight into the mechanism of ventricular remodeling after AMI and reveal that CaSR is a novel treatment target for ventricular remodeling. The conclusion of this study may provide scientific evidence for the effective treatment of heart failure.

心室重塑是心肌梗死后心力衰竭的基本机制和主要原因，如何逆转是医学难题。近年研究发现，在急性心肌梗死（AMI）发展过程中，有T细胞浸润及细胞因子释放，但对其在心室重塑中的作用及机制缺乏研究。我们首次发现： AMI大鼠心肌组织CD4+T 细胞浸润，钙敏感受体（CaSR）表达增加，NLRP3炎症体活化，发生心肌纤维化。综上提出假设"AMI时CD4+ T细胞中CaSR的激活，活化NLRP3炎症体，引起IL-1?等细胞因子释放，通过成纤维细胞的相应受体，导致心肌纤维化和心室重塑"。本课题拟通过AMI患者、模型大鼠以及共培养细胞模型为研究对象，观察CD4+T细胞CaSR表达、NLRP3炎症体活化和炎症因子释放的变化规律及信号通路，阐明上述环节在心室重塑中的作用，从新的视角揭示AMI后心室重塑的发生机制，而抑制CaSR可能成为防治心室重塑的新靶点。本研究成果将为心力衰竭的有效防治提供科学依据。

心室重塑是心肌梗死（myocardial infarction，MI）后心力衰竭的基本机制和主要原因，如何逆转是医学难题。近年研究发现，在MI发展过程中，有免疫细胞浸润及细胞因子释放，但对其在心室重塑中的作用及机制缺乏研究。本课题组以MI患者及MI大鼠获得的外周血CD4+T细胞、中性粒细胞以及腹腔巨噬细胞为研究对象，以形态学、病理学、分子生物学等为手段，使用CaSR激动剂和抑制剂干预后，观察人外周血CD4+T细胞、外周血中性粒细胞、大鼠心肌组织、巨噬细胞的CaSR、胞内钙流、NLRP3炎性体、细胞因子的表达及其信号传导途径，分析CaSR的变化与MI后心室重塑的内在关系，提示CaSR激活可通过增加免疫细胞内钙超载、NLRP3炎性体激活、细胞因子分泌增加及成纤维细胞表型转化，参与MI导致的心室重塑过程；而抑制CaSR表达可减轻上述环节。故MI可能通过CaSR介导的免疫细胞胞内钙超载引起NLRP3炎性体激活和细胞因子分泌增加从而导致心室重塑，抑制CaSR可能成为防治心室重塑的新靶点，为研究免疫细胞在MI后心室重塑的机制提供新思路，为其防治及新药开发提供新靶点。