心肌纤维化是糖尿病心肌病的典型病理特征之一，其发病机制未明。心肌细胞与成纤維细胞相互交流可以影响彼此的功能，但是，目前不清楚心肌细胞能否影响成纤维细胞的功能而参与糖尿病心肌纤維化。本研究假设是糖尿病高血糖致心肌细胞增加HMGB1的表达和释放，并进一步通过旁分泌作用于成纤維细胞TLR4受体，导致成纤維细胞IL-33表达下调，促进成纤維细胞胶原蛋白合成增加、心肌纤维化。我们将用链佐星诱发小鼠糖尿病和高糖刺激心肌细胞-心肌成纤维细胞共培养系统， 用细胞和分子生物学手段从以下几方面探索糖尿病心肌病的发病机制：1）研究心肌细胞是否通过影响成纤维细胞功能而参与糖尿病心肌病的形成；2）明确糖尿病时心肌细胞是否通过HMGB1/TLR4/IL-33 细胞外信号链影响成纤维细胞的功能；3）探索HMGB1/TLR4/IL-33 细胞外信号链参与糖尿病心肌纤维化发生的分子机制。研究结果将为该病的治疗提供新思路。

One of the hall mark pathological features of diabetic cardiomyopathy is myocardial fibrosis. However, the detailed mechanism involved in the development of myocardial fibrosis in diabetes mellitus (DM) is not clear. Cell-cell communication between cardiomyocyte and cardiac fibroblast has been reported plays important roles in heart development and myocardial remodeling. Whether the cardiomyocyte-fibroblast communication plays role(s) in the pathogenesis of diabetic cardiomyopathy remains unknown. Our preliminary study indicates that myocardial levels of HMGB1 is increased while the levels of IL-33 is decreased in mice with DM. Based on the preliminary data we hypothesized that DM promotes cardiomyocytes to increase HMGB1 expression and releasing by which interacts with TLR4 of cardiac fibroblasts via paracrine. The resultant of the cardiaomyocyte-cardac fibroblast interaction is down regulation of IL-33 expression in cardiac fibroblasts. The decreased myocardial IL-33 could promote cardiac fibroblast collagen expression, myocardial fibrosis and the development of diabetic cardiomyopathy. We will use mouse model of DM and treating cardiomyocyte-cardiac fibroblast co-culture system with high glucose to test the hypothesis. 　　 The proposed study includes following specific aims: 1) to determine whether the cardiomyocytes can interact with the cardiac fibroblasts and actively paticipate in the pathogenesis of diabetic cardiomyopathy by affacting the function of the cardiac fibroblasts. 2) to evaluate whether cardiomyocytes interact with cardiac fibroblasts through extracellular HMGB1/TLR4/IL-33 axis. 3) to explore the role of extracellular HMGB1/TLR4/IL-33 axis in collagen production by cardiac fibroblasts in the diabetic condition and the signaling pathway involved in collagen expression. Specifically， we will target the DGKzeta/DAG/PKCbeta pathway. The results of this proposal will provide us with novel strategic information for the treatment of the diabetic cardiomyopathy.