RNA可变剪接分子RBM22介导的心肌细胞代谢和炎症调控在慢性心衰发生中的作用及机制研究

炎症是非缺血性慢性心衰发生中的关键事件，但在免疫细胞活化之前，非缺血性应激导致的心脏组织起始期炎症如何启动和调节，尚存很多未知。研究表明心肌细胞感应压力负荷等应激后产生炎性因子和趋化因子，启动起始期炎症反应，驱动慢性心衰后期病理进程。我们预实验发现在主动脉弓缩窄模型早期，RNA可变剪接分子RBM22心肌细胞特异敲除小鼠中心肌细胞介导的炎性因子和趋化因子产生增加，导致后期心肌纤维化加重，心功能恶化。而且RBM22缺陷上调炎性因子和趋化因子启动子区组蛋白乙酰化水平，促进心肌中代谢产物乙酰辅酶A的产生，其可能与乙酰辅酶A代谢酶基因发生可变剪接生成功能异常的异构体有关。据此我们将深入验证假说：RBM22改变压力负荷下心肌细胞的代谢状态，抑制心肌细胞介导的起始期炎症始动，从而控制心衰的进展，并从可变剪接、代谢及表观三方面协同阐明其分子机制，为非缺血性慢性心衰的早期干预提供潜在的免疫调节治疗策略。

Inflammation plays a key role in the nonischemic chronic heart failure. However, the molecular mechanism by which the early inflammation in cardiac tissue triggered by nonischemic stresses and generated before the activation of immune cells is initiated and regulated has not been established. Previous studies show that cardiomyocytes can produce inflammatory cytokines and chemokines in response to the pressure overload stress, and then initiate early inflammatory responses, which drivers the latter progression to nonischemic heart failure. Our data from the preliminary experiments showed that cardiac-specific RBM22 (an RNA alternative splicing factor) knockout mice exhibited significantly increased production of inflammatory cytokines and chemokines in cardiomyocytes at early times after transverse aortic constriction (TAC), which resulted in the severer cardiac fibrosis and dysfunction at later times. RBM22 deficiency increased the histone acetylation levels in the promoters of inflammatory cytokine and chemokine genes, and promoted the production of metabolite acetyl-CoA in cardiac tissue, which may attributed to the dysfunctional isoforms of acetyl-CoA metabolic enzymes generated by RBM22-mediated mRNA alternative splicing. Thus, we will test the hypothesis that the altered metabolic state in cardiomyocytes mediated by RBM22 in response to pressure overload suppresses the initiation of early cardiac inflammatory responses leading to preventing the progression of heart failure. We will further investigate the underlying mechanism of RBM22-mediated inflammation regulation in heart failure from a comprehensive view of alternative splicing, metabolism and epigenetics, which may offer a potential immunomodulatory therapeutic strategy for early intervention of the nonischemic chronic heart failure.