PRDM16调控EndMT介导的糖尿病心肌病的机制研究

Diabetic cardiomyopathy is one of the important diabetic cardiovascular complications.Myocardial fibrosis is the main pathological characteristics of diabetic cardiomyopathy. Recent studies have shown that high glucose induced endothelial to mesenchymal transition (EndMT) is closely related to the occurrence and development of diabetic cardiac fibrosis. Blockade of EndMT can effectively prevent diabetic myocardial fibrosis .PRDM16 is a member of the PR domain—containing protein family. Recent studies confirm that PRDM16 is closely related to a variety of congenital heart disease and myocarditis, but whether that PRDM16 directly involved in the pathogenesis of diabetic cardiomyopathy is not yet reported.Our preliminary experiments showed that PRDM16 expressed in human aortic endothelial cells. Overexpression of PRDM16 can reverse high glucose-induced endothelial to mesenchymal transition (EndMT). Additionally, we found that PRDM16 enhance interaction of Smad3 with HDAC1,which inhibited Smad3 downstream signals. This study applies PRDM16 endothelial specific knockout and over expression mice to prove our hypothesis, so as to provide new therapeutic targets for the prevention and treatment of diabetic cardiomyopathy .

糖尿病心肌病是重要糖尿病心血管并发症之一，以心肌间质纤维化是其主要病理特征。近期研究显示高糖诱导的内皮细胞间充质化（EndMT）与糖尿病心肌纤维化的发生及发展密切相关，抑制EndMT可以有效的阻止糖尿病心肌纤维化。PRDM16是PR结构域家族的第16个成员，新近研究证实PRDM16与先心病及心肌炎密切相关，但PRDM16是否直接参与糖尿病心肌病的发病尚未报道。我们预实验发现，PRDM16显著表达于人主动脉内皮，过表达PRDM16可以逆转高糖诱导的内皮细胞间充质化，且这一作用可能是通过促进HDAC1与Smad3相结合形成无活性转录复合体，进而抑制Smad3下游通路实现的。本课题拟应用PRDM16内皮特异性敲除及过表达小鼠和野生小鼠的糖尿病动物模型及细胞模型（高糖），从整体-细胞层次证明我们的假说，从而为糖尿病心肌病防治提供新的思路及治疗靶点。

糖尿病心肌病是重要糖尿病心血管并发症之一，以心肌间质纤维化是其主要病理特征。近期研究显示高糖诱导的内皮细胞间充质化(EndMT)与糖尿病心肌纤维化的发生及发展密切相 关，抑制EndMT可以有效的阻止糖尿病心肌纤维化。PRDM16是PR结构域家族的第16个成员，新 近研究证实PRDM16与先心病及心肌炎密切相关，但PRDM16是否直接参与糖尿病心肌病的发病尚 未报道。我们预实验发现，PRDM16显著表达于人主动脉内皮，过表达PRDM16可以逆转高糖诱导 的内皮细胞间充质化，且这一作用可能是通过促进HDAC1与Smad3相结合形成无活性转录复合体 ，进而抑制Smad3下游通路实现的。我们研究发现，PRDM16通过PPARγ通路及自噬改善PA诱导的内皮细胞炎症。此外我们研究还发现，Mof介导的H4K16ac直接结合在Pax6和Foxa2的启动子区域。抑制Mof乙酰化活性并使H4K16ac减少，可以增加α细胞凋亡并使其功能减退，最终影响血糖代谢。上述研究成果为糖尿病及其并发症的治疗提供了新的靶点和思路，为糖尿病的机制研究也提供了相应的理论依据。