肝脏特异性miR-122通过TGFβ-EndMT途径缓解动脉粥样硬化的发生

Endothelial injury is the initiative step of atherosclerosis, and endothelial-to-mesenchymal transition (EndMT) is involved in the development and progression of atherosclerosis. miR-122 is a liver-specific microRNA. We have found that miR-122 is down-regulated in the liver tissue of ApoE-/- mice induced by high fat diet and was up-regulated in serum and in arterial tissues. The expression of miR-122 is also increased during the H2O2-induced endothelium-to-mesenchymal transition (EndMT). miR-122 inhibitor induces the development of EndMT, while miR-122 mimic inhibits TGFβ1/TGFβR1 expression, and inhibits the H2O2-induced EndMT. We hypothesize that miR-122 may enter the blood circulation from the liver to the arterial intima and arterial tissue, to prevent the development of atherosclerosis through TGFβ-EndMT pathway. To test our hypothesis, we will use ApoE-/- mice with lentivirus-miR-122 or lentivirus-anti-miR-122, miR-122 knockout rats, miR-122 knock out mice, and endothelial cells of different species, to investigate the role and mechanism of miR-122 in the development of atherosclerosis via EndMT. This study will provide a novel strategy for the prevention and therapy of atherosclerosis.

内皮细胞损伤是动脉粥样硬化发生的使动环节，内皮向间质转化（EndMT）参与了动脉粥样硬化的发生和发展。我们前期研究发现miR-122在高脂饮食诱导的ApoE-/-小鼠动脉粥样硬化模型肝组织中表达下调，在血清和动脉中表达上调；在双氧水诱导的EndMT过程中其表达也出现上调；抑制miR-122可以诱导EndMT的发生，而过表达miR-122可以抑制TGFβ1/TGFβR1的表达，抑制双氧水诱导的EndMT。由此我们假设，miR-122有可能从肝脏进入到血循环进而作用于动脉内膜及动脉组织，通过TGFβ-EndMT途径抑制动脉粥样硬化的发生。本课题拟采用ApoE-/-小鼠，外源性给予过表达或敲减miR-122的慢病毒，同时利用已构建的miR-122基因敲除大鼠和小鼠，及不同种属内皮细胞，研究miR-122通过EndMT对动脉粥样硬化发生发展的作用及其相关分子机制，为动脉粥样硬化的防治提供新思路。

动脉粥样硬化是严重威胁人类生命健康的心血管事件之一，内皮损伤是动脉粥样硬化发生的使动环节，研究表明内皮向间质转化（EndMT）通过促进胶原形成和增加内皮细胞通透性促进了动脉粥样硬化的发生和发展。找到能够调控或逆转EndMT的分子至关重要。. 本研究致力于探讨miR-122在EndMT和动脉粥样硬化发生发展过程中的作用机制。结果显示，和对照组相比，动脉粥样硬化小鼠血浆和动脉组织中miR-122表达水平明显增加，而其肝脏组织中miR-122表达水平明显降低；细胞实验结果证实miR-122在H2O2诱导的EndMT发生过程中也出现了表达的增加。进一步利用促进和抑制miR-122表达的慢病毒和miR-122基因敲除小鼠进行实验，结果发现促进miR-122表达能够促进EndMT的发生和动脉粥样硬化斑块的形成，而抑制或敲除miR-122则能够抑制EndMT的发生并缓解动脉粥样硬化的发生和发展。另外细胞实验证实miR-122能够通过靶向调控NPAS3的表达调控H2O2诱导的EndMT的发生。. 总之，本研究证实miR-122可能通过靶向调控NPAS3的表达在EndMT介导的动脉粥样硬化发生发展过程中发挥重要作用，进而参与动脉粥样硬化早期的病理过程。本研究为动脉粥样硬化的防治提供新的理论依据和潜在的治疗靶点。