GLP-1/beta-catenin/TCF信号通路对糖尿病鼠心肌细胞凋亡的保护作用及机制研究

Diabetic cardiomyopathy (DC) is a long-term complication of diabetes. Increasing lines of evidence have shown that therapeutics against cardiomyocyte apoptosis significantly delay the progression of DC. The canonical β-catenin/TCF signaling pathway is important in the modulation of cell proliferation and survival. GLP-1 can inhibit the apoptosis of pancreatic β-cells and induce the proliferation and regenesis of β-cells via the activation of β-catenin/TCF signaling. Recently, GLP-1 has been shown to exert cardiovascular effects in a number of experimental models. Nevertheless, the protective effect of GLP-1 on the cardiomyocyte apoptosis in DC and its underlined mechanism remain largely unknown thus far. GLP-1 receptors are expressed in cardiomyocytes, while the activation of β-catenin/TCF signaling leads to the inhibition of cardiomyocyte apoptosis in DC. We therefore proposed that GLP-1 might protect the cardiomyocyte from apoptosis via activating β-catenin/TCF signaling pathway. The aim of this study is to clarify the protective effect of GLP-1 on the cardiomyocyte apoptosis in high-gluocose culture condition in vitro, and its effect on the diabetic cardiomyopathy in STZ induced diabetic rats in vivo, respectively; to further investigate the role of GLP-1/β-catenin/TCF signaling in the inhibition of cardiomyocyte apoptosis and its underlying mechanims. These findings may raise new possibilities and therapeutic target for treatments of DC.

糖尿病心肌病是糖尿病严重的慢性并发症之一。研究表明给予实验对象抗心肌凋亡治疗能有效控制糖尿病心肌病的病程进展。β-catenin/TCF信号通路是调控细胞生存的重要通路。GLP-1通过激活β-catenin/TCF通路抑制胰岛β细胞凋亡，促进β细胞增殖和再生。研究显示GLP-1对心血管具有一定保护作用。然而对GLP-1在糖尿病所致心肌细胞凋亡中的作用及具体机制目前所知甚少。已发现GLP-1受体在心肌细胞广泛表达，而β-catenin/TCF通路活性增强可抑制糖尿病心肌细胞凋亡，提示GLP1可能通过激活β-catenin/TCF通路抑制心肌细胞凋亡。本课题拟明确：GLP-1对高糖培养所致大鼠心肌细胞凋亡及STZ糖尿病大鼠心肌病变的保护作用；GLP-1/β-catenin/TCF通路在保护高糖所致大鼠心肌细胞凋亡中的作用及具体调控机制。本研究将为糖尿病心肌病的预防和治疗提供新的思路和治疗靶点。

心肌细胞凋亡在糖尿病心肌病进展中发挥重要作用。研究显示GLP-1对心血管具有一定保护作用。然而对GLP-1在糖尿病所致心肌细胞凋亡中的作用及具体机制目前所知甚少。本研究首次报道了1）高浓度棕榈酸诱导的心肌细胞凋亡与β-catenin信号通路活性降低相关；2）GLP-1通过恢复β-catenin信号通路活性抑制棕榈酸诱导的心肌细胞凋亡；3）GLP-1抗心肌凋亡的作用依赖于对GLP1R Akt/GSK3b介导的β-catenin信号通路活的激活；4）GLP-1通过激活Akt抑制棕榈酸诱导的CD36膜转位和心肌细胞内中性脂肪堆积；5）整体动物实验结果证实GLP-1的长效激动剂Exenatide通过激活Akt/GSK3β/β-catenin通路逆转2型糖尿病小鼠心肌病变和心功能缺陷。该研究结果提示β-catenin信号通路可能成为糖尿病心肌病治疗的新靶点，并为临床使用GLP-1药物保护心脏功能提供新的理论依据。