心肌纤维化是糖尿病性心肌重构的重要方面， 但发生机制不明。我们证实发生纤维化的糖尿病db/db小鼠心肌中去乙酰化酶SIRT1和巨噬细胞移动抑制因子（MIF）分别显著降低和升高，SIRT1和MIF在心肌成纤维细胞中存在彼此负调控作用。推测MIF通过MIF-CD74-MAPK轴负调控SIRT1蛋白表达，活化Smad3并调控细胞外基质(ECM)相关基因表达；SIRT1降低使心肌消除活性氧簇(ROS)能力下降、去乙酰化NF-kB、AP1和Smad3减少，进而促进MIF表达、MIF信号通路激活和ECM相关基因表达。本课题将利用db/db小鼠和db/m小鼠，MIF基因敲除小鼠、C57BL/6小鼠及其心肌成纤维细胞，从整体-细胞-分子水平，研究SIRT1与MIF信号通路的交互作用，评价增强心肌SIRT1表达，抑制MIF表达对心肌纤维化的治疗作用，为进行糖尿病性心肌纤维化的治疗研究提供科学依据和资料。

Myocardial fibrosis is the most important aspect in diabetic cardiac remodeling, but the mechanism underlying is not well elucidated. Our previous study showed that silent mating type information regulation 2 homolog-1 (Sirtuin1, SIRT1) protein was markedly decreased, and macrophage migration inhibitory factor（MIF）was markedly increased in the myocardium of 18-week-old diabetic db/db male mice with obvious myocardial fibrosis.A mutual negative regulation was found between SIRT1 and MIF in mouse cardiac fibroblasts.We hypothesize that MIF activates Smad3 to modulate ECM-related genes expression and negatively modulates SIRT1 protein expression via MIF-CD74-MAPK axis. Down-regulation of SIRT1 decreases the deacetylated forms of NF-kB, AP1 and Smad3, and reduces the level of reactive oxygen species(ROS) in cardiomyocytes, contributing to MIF expression, activation of MIF signaling pathway and ECM-related genes expression. The diabetic db/db male mice, MIF-knockout(MIF-KO) male mice and C57BL/6 male mice, and cardiac myofibroblasts derived from the adult MIF-KO male mice and adult C57BL/6 male mice will be used in the present project. We will study the roles of SIRT1 and MIF, cross-talk between SIRT1 and MIF signalling pathway in the process of diabetic myocardial fibrosis at the whole organism, cellular and molecular level,respectively. The effects of myocardium-specific over-expression of SIRT1 and suppression of MIF will be evaluated on the therapy effectiveness of diabetic myocardial fibrosis in diabetic db/db male mice. The present study is expected to provide scientific evidence and material for future therapy research on diabetic myocardial fibrosis.