不规则趋化因子在糖尿病心功能损害代谢记忆中的作用及机制

Metabolic memroy of cardiac dysfuntion has been confirmed in diabetes mellitus patiens. The prognosis in these patients is poor and there is no effective therapy for metabolic memory of cardiac dysfuntion. We have reported that Fractalkine (FKN) exacerbated heart failure via promotion of cardiomyocytes apoptosis and cardiac fibrosis, and direct inhibition of FKN miproved cardiac funtion. Our preliminary experiments showed that: (1) FKN experssion was enhanced in cardiomyocytes in response to high gluocose exposure; (2) In comparsion of wild type mice, cardiac function were perserved in CX3CR1 deficiency mice with diabetes mellitus. And the improved effects of CX3CR1 deficiency on cardiac funtion in diabetic mice was independent of glucose levels.Accordingly ,we hypothesized that FKN might be an important chemokine to promote metabolic memory of diabetic cardiac dysfuntion through cell apoptosis and fibrosis.To test this hypothesis, we are to determine the effect of FKN on funtion of cardiomyocytes and fibroblasts and explore the underlying mechanisms in this project.Streptozotocin-induced type 1 diabetes mellitus mice and db/db transgenic type 2 diabetes mellitus mice are the main pathological models. FKN receptor (CX3CR1) knockdown in cardiomyocytes and fibroblasts as well as knockout mice will be employed.We will use both in vitro and in vivo experiments coming with CX3CR1 Knockout and FKN neutralizing antibody treatment to clarify the signal pathways responsible for the detrimental roles of FKN on cardiomyocytes apoptosis, fibrosis and metabolic memory of diabetic cardiac dysfunction.This study would provide new insight into the metabolic memory and lead to new therapeutic target for metabolic memory of daibetic cardiac dysufntion.

糖尿病患者存在心功能损害"代谢记忆"，预后不良，目前无有效治疗方法。我们最近的研究和预实验结果证实：（1）不规则趋化因子（FKN）可促进心肌细胞凋亡和纤维化加重心衰，抑制FKN可以改善心功能；（2）高糖上调心肌细胞FKN表达水平；（3）对比野生型小鼠，FKN特异性受体CX3CR1敲除的1型糖尿病小鼠心功能明显改善并独立于血糖水平。因此我们假设FKN可能通过诱导心肌细胞凋亡和心肌纤维化参与糖尿病心功能损害"代谢记忆"。本项目拟在细胞水平明确FKN对心肌细胞及纤维细胞的作用及机制，建立链脲佐菌素诱导的1型糖尿病小鼠模型和db/db转基因2型糖尿病小鼠模型验证上述假设。通过沉默或敲除CX3CR1、FKN中和抗体治疗等在细胞和动物水平反证FKN对心肌细胞凋亡、纤维化及心功能的影响，确认FKN在糖尿病心功能损害"代谢记忆"的可能信号通路，为寻找治疗新靶点提供理论依据。