MLL4介导的H3K4甲基化对糖尿病血管重构的作用及机制研究

Coronary heart disease is the leading cause of morbidity and mortality in people with diabetes mellitus. A lot of clinical trials found intensive glucose control cannot reduce the risk of cardiovascular events in diabetes, attributing to epigenetic changes induced by impaired glucose metabolism. Previous and our prophase research work revealed histone H3 lysine 4 (H3K4), a major epigenetic modification site, was specifically regulated by methyltransferase MLL4. Furthermore, this process may participate in abnormal activation of vascular cells under diabetes. In present study, we attempt to (1) detect the effect and potential mechanism of MLL4 knock-down on vascular smooth muscle cells and endothelial cells stimulated by high glucose, in order to explore the advantage of MLL4 for specificity of vascular smooth muscle cell and multiple target sites; (2) establish carotid artery balloon injury model in tye 2 diabetic rats, and evaluate the effects of local MLL4 down-regulation on neointimal hyperplasia and re-endothelialization, so as to investigate the role of H3K4 methylation mediated by MLL4 plays in diabetic vascular remodeling. On the basis of successful application of our research program, the relationship and potential mechanism between epigenetics and diabetic vascular remodeling will be further elucidated, and an optimal therapeutic strategy of diabetic vascular complication will be provided.

冠心病是糖尿病致死致残的首要因素，多项临床研究显示强化降糖治疗并不能降低糖尿病患者的心血管事件风险，其原因可能与糖代谢异常介导的表观遗传学改变有关。既往和前期研究工作发现，组蛋白H3K4是机体主要的表观遗传学修饰位点，受甲基化酶MLL4特异性调节，这一过程可能参与了糖尿病环境下血管细胞的病理性活化。本项目组拟通过（1）检测下调MLL4对高糖诱导下血管平滑肌细胞和内皮细胞功能的影响及内在机制，探讨MLL4介导的H3K4甲基化是否具有 “平滑肌细胞特异性”和“干预位点多样性”；（3）构建2型糖尿病大鼠颈动脉球囊损伤模型，检测局部下调MLL4对血管内膜增生和内皮化的影响，探讨MLL4介导的H3K4甲基化对糖尿病血管重构的作用。通过本项目的实施，可进一步阐明表观遗传学与糖尿病血管重构的关系和机制，为糖尿病血管并发症的防治提供新的治疗策略。

以冠状动脉病变为基础的心血管事件是糖尿病患者致死、致残的首要原因。多项临床研究显示强化降糖治疗并不能降低糖尿病患者的心血管事件风险，其原因可能与糖代谢异常介导的表观遗传学改变有关。既往和前期研究工作发现，组蛋白H3K9、H3K4是机体主要的表观遗传学修饰位点，分别受甲基化酶suv39h1和MLL4（Kmt2d）的特异性调节。Suv39h1通过诱导靶基因启动子区组蛋白H3K9三甲基化发挥转录抑制效应；Kmt2d通过诱导基因启动子区H3K4三甲基化而发挥转录活化效应。组蛋白甲基化修饰这一表观遗传学现象可能参与了糖尿病环境下血管细胞的病理性活化。通过本项目的研究发现：（1）下调suv39h1可抑制高糖及血管紧张素诱导下血管平滑肌细胞的病理性增殖和迁移；（2）局部下调suv39h1可拮抗2型糖尿病大鼠颈动脉球囊损伤后新生内膜形成；（3）下调Kmt2d可抑制高糖诱导下血管平滑肌细胞的增生和迁移；（4）局部下调Kmt2d可拮抗血管内膜增生。通过本项目的实施，为进一步明确表观遗传学与糖尿病血管重构的关系提供了理论依据，为糖尿病血管并发症的防治策略提供了新的思路。