Sirt6是与衰老和炎症密切相关的核去乙酰化酶。心梗后左室发生的炎症修复重塑是心梗后心血管事件的主要诱因。肥大细胞是心梗修复过程中维持炎症微环境平衡、调节纤维化重塑的关键免疫细胞。我们拟在Sirt6保护心脏急性缺血/再灌损伤研究的基础上，构建Sirt6+/-小鼠冠脉左前降支结扎诱导的左室纤维化重塑模型以及离体培养的Sirt6敲除和过表达的小鼠肥大细胞活化模型，研究Sirt6通过直接抑制肥大细胞活化，进而间接抑制成纤维细胞功能和纤维化重塑的创新作用模式。进一步利用IP/coIP、EMSA及ChIP等实验技术，探索Sirt6与肥大细胞NF kB/AP-1的相互作用，阐明NF kB/AP-1招募Sirt6至下游促炎因子基因的启动子区，减低H3K9的乙酰化状态，抑制促炎基因的转录和表达，进而改善炎症微环境、抑制成纤维细胞活化，拮抗心梗损伤后纤维化重塑的作用及机制，为心梗重塑的防治提供新的治疗策略。

Sirt6 is a deacetylase in nuclear closely related to aging and inflammation. The inflammatory repair and remodeling in left ventricles after myocardial infarction is a major cause of cardiovascular events in the prognosis of myocardial infarction. Mast cells are the key immune cells in maintaining the homeostasis of the inflammatory microenvironment, and regulating the fibrotic remodeling in the repair process after myocardial infarction. By using a left ventricular fibrotic remodeling mouse model induced by left anterior descending coronary artery ligation in Sirt6+/- and WT mice, as well as the activated cell models of primary cultured murine mast cells with Sirt6 gene knockout or overexpression, we propose to reveal a new protection of Sirt6 against cardiac remodeling by suppressing the activation of mast cells directly, and then inhibiting the functions of fibroblasts and fibrosis remodeling stirred by inflammatory stimuli indirectly. We further explore the interaction between Sirt6 and NF kB/AP-1 in mast cells by using IP/coIP, EMSA and ChIP experiments, to reveal how NF kB/AP-1 recruits Sirt6 to the promoter regions of their downstream proinflammatory cytokine genes, and then reducing H3K9 acetylation levels to suppress the transcription and expression of the proinflammatory genes. Furthermore, Sirt6 improves the inflammatory microenvironment, inhibits fibroblast activation and antagonizes fibrotic remodeling injury after myocardial infarction. Our study will provide a new therapeutic strategy for the treatment of fibrotic remodeling after myocardial infarction by Sirt6 activation.