内皮细胞Nogo-B在高血压诱发冠状动脉粥样硬化过程中的作用与机制

Hypertension is an established powerful risk factors for coronary atherosclerosis, the leading cause of myocardial infarction. Despite of intense research for several decades, the underlying molecular mechanisms of hypertension inducing coronary atherosclerosis keep poorly understood. Recently, we discovered that endothelial Nogo-B regulates vascular functions in hypertension and pressure overload-induced heart failure. Interestingly, Nogo-B expression was down-regulated in atherosclerotic lesions in patients. In this proposal, we aim to explore the role of Nogo-B in the development of hypertension-induced coronary atherosclerosis by employing a novel model of coronary atherosclerotic lesions induced by hypercholesterolemia and hypertension, well-known risk factors for atherosclerosis. To this aim, transverse aortic constriction (TAC) surgery was performed in mice lacking endothelial Nogo-B in ApoE-/- background with ApoE-/- mice as control. As indicated by the preliminary data, ApoE-/- mice developed coronary atherosclerotic lesions within 6 weeks following TAC, (without the need of long-term high-cholesterol diet) and 26.67% of the mice died of MI at 6-week post-TAC, while mice lacking Nogo-B specifically in endothelial cells were markedly resistant to the development of coronary atherosclerotic lesions and MI. By in vivo and in vitro examining the modifications of endothelial S1PR1 activities and surface abundance of vascular adhesion molecule, ICAM-1 and VCAM-1, we attempt to illuminate that in the absence of endothelial Nogo-B, the biosynthesis of sphingolipids, particularly S1P, is upregulated and activates S1PR1, protecting the endothelium from hypertension and hypercholesterolemia-triggered vascular inflammation and atherogenesis. This study will identify an important and novel role of endothelial Nogo-B-dependent regulation of sphingolipid de novo biosynthesis in the coronary atherosclerosis, which could be helpful in developing effective interventions to prevent and treat myocardial infarction.

高血压是诱导冠状动脉粥样硬化发生的重要危险因素，但其分子机制尚未完全阐明。申请人研究表明内皮细胞Nogo-B通过抑制鞘磷脂合成在高血压及心衰中起重要作用，临床研究表明其可能参与动脉粥样斑块的形成。假设：压力超负荷早期，血管内皮Nogo-B表达瞬时上调，通过抑制S1P-S1PR1信号通路，促进细胞表面黏附因子表达，始动冠状动脉粥样硬化的发生。本项目拟在ApoE敲除小鼠上施行主动脉弓缩窄手术，建立新的压力超负荷致冠状动脉粥样硬化及心梗模型，并通过内皮特异敲除Nogo-B，以冠状动脉粥样斑块大小和心梗面积为指标，研究Nogo-B在该过程中的作用；结合体内报告基因观测和体外机制研究，探索Nogo-B如何抑制内皮细胞S1P-S1PR1信号通路，进而上调细胞表面黏附因子的表达。研究结果不仅可以阐明内皮细胞Nogo-B在高血压诱导冠状动脉粥样硬化中的作用与机制，也将为冠心病的预防与早期治疗提供新的线索。

高血压是诱导冠状动脉粥样硬化发生的重要危险因素，但其分子机制尚未完全阐明。申请人前期研究表明内皮细胞Nogo-B通过抑制鞘磷脂合成在高血压及心衰中起重要作用，临床研究表明其可能参与动脉粥样斑块的形成。本项目拟研究压力超负荷早期，血管内皮Nogo-B表达瞬时上调，促进细胞表面黏附因子表达，始动冠状动脉粥样硬化发生发展的分子机制。本项目在ApoE敲除小鼠上施行主动脉弓缩窄手术，建立新的压力超负荷致冠状动脉粥样硬化及心梗模型，并通过内皮特异敲除Nogo-B，以冠状动脉粥样斑块大小和心梗面积为指标，研究Nogo-B在该过程中的作用；结合体内全心脏切片冠脉斑块观测和体外机制研究，探索Nogo-B如何激活内皮细胞S1P-S1PR1及P38MAPK-P65炎症信号通路，影响内质网-线粒体相互作用，促进线粒体ROS产生，进而上调细胞表面黏附因子的表达。研究结果不仅可以阐明内皮细胞Nogo-B在高血压诱导冠状动脉粥样硬化中的作用与机制，也将为冠心病的预防与早期治疗提供新的线索。

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