Notch-Pin1通路在内皮损伤中的作用及白藜芦醇抗动脉粥样硬化的机制研究

Atherosclerosis is the common cause of acute cardiovascular events, with a complex pathogenesis. Recent studies have revealed Notch-Pin1 pathway plays an important role in ischemic stroke, by modulating cell apoptosis. Our preliminary experiments showed the expression level of Pin1 was significantly elevated in aorta of LDLR(-/-) mice with high-cholesterol diet. Until now, little is known about the function of Notch-Pin1 in endothelial damage and atherosclerosis. Resveratrol has been reported to modulate the lipid metabolism and inhibit inflammation via activating Sirt1 expression, thereby, exerts cardiovascular protective effects. It remains to be elucidated that whether resveratrol biological effects are associated with the Notch-Pin1 pathway. The aim of this project is to investigate the impact of Notch-Pin1 in endothelial damage and explore the related mechanism of resveratrol in atherosclerosis. This study would potentially provide an experimental evidence for resveratrol in atherosclerosis prevention.

动脉粥样硬化常常导致急性心血管事件的发生，其发病机制复杂。新近研究认为Notch和Pin1通路在缺血性卒中的细胞凋亡中具有调控作用。本课题组前期实验发现，高脂诱导的LDLR敲除小鼠的Pin1蛋白表达增加，但其是否参与了血管内皮细胞损伤，从而导致动脉粥样硬化形成，目前尚未完全阐明。白藜芦醇可激活Sirt1调节脂质代谢和抑制炎症反应等多种心血管保护效应，但这种效应是否与Notch和Pin1/NF-κB信号通路有关，有待证实。本课题旨在探索Notch-Pin1信号通路在内皮细胞损伤中的机制，进一步明确白藜芦醇抗动脉粥样硬化的分子机制与Notch-Pin1通路间的关系，为临床防治动脉粥样硬化疾病奠定实验基础。

血管内皮细胞损伤及凋亡是动脉粥样硬化（AS）的始动环节，对动脉粥样硬化的发生发展具有决定性作用。在高脂喂养LDLR-/-小鼠动脉组织和TNF-α诱导内皮细胞损伤中均发现Notch1和Pin1表达上调，Notch1可调控Pin1的表达。探究Notch1和Pin1信号通路在内皮细胞损伤中的作用，进一步探明白藜芦醇抗动脉粥样硬化的机制是否与Notch1-Pin1通路相关。白藜芦醇干预后通过激活SIRT1，下调Notch1、Hes1和Pin1的表达，抑制炎症因子VCAM-1和NF-κB p65的产生，缩小动脉斑块面积，改善血管内皮功能，抑制动脉粥样硬化斑块发展。通过对基因芯片的分析，发现AS主动脉中Hedgehog通路分子表达下调，激活Shh通路可通过抑制NF-κB p65核转位，下调ICAM-1和VCAM-1、ROS、Bcl-2的表达，从而改善内皮功能和凋亡，提示Shh可能作为一种保护性因子，具有减轻动脉粥样硬化效应。本课题组还发现丹参多酚酸酯通过抑制心肌细胞NFATc3核转位，抑制CaNA的表达、CaN的活性，下调β-MHC表达，改善心梗后心肌重塑。而组织激肽释放酶-1基因可能通过抑制心肌中MIF、MMP-2、MMP-9表达，部分逆转心梗大鼠的左室重塑。