低切应力诱导的miR-200c通过靶标SIRT1调节内皮细胞炎症反应

Low shear stress(LSS) plays an important role in the pathogenesis of atherosclerosis, the mechanism of which remains incompletely understood. MicroRNA(miRNA) has been proven to be involved in the physiological regulation of flow on gene expression in endothelial cells(ECs). However, to our knowledge, the potential involvement of miRNA in the regulatory effects of LSS on the pathogenesis of atherosclerosis has thus far never been investigated. In our previous studies, we have found that LSS signi?cantly increased the expression of miR-200c, and that stable transfection of miR-200c signi?cantly decreased the expression of eNOS, while increasing the expression of some endothelial adhesion molecules(VCAM1, ICAM1) as well as leukocyte adherence to ECs. Based on these preliminary results, our present study was conducted to further investigate whether LSS-induced miR-200c modulates ECs inflammation via Sirt1 and its downstream eNOS and NFκB signal pathways. The results will reveal a new mechanism by which LSS modulates gene expression and inflammation in ECs, and will be helpful for further elucidation of the molecular mechanisms of LSS-mediated atherosclerosis, which will provide theoretical guidances for the prevention and treatment of atherosclerotic diseases.

低切应力在动脉粥样硬化血管损伤的发生机制中起重要作用，但其调控机制尚不明确。microRNA(miRNA)介导着生理切应力对血管内皮细胞（ECs）功能调控，但迄今针对miRNA是否参与低切应力对ECs功能的调控还不清楚。我们的研究发现：低切应力显著诱导ECs miR-200c表达上调，体外过表达miR-200c可下调ECs eNOS的水平，促进NFκB p65亚基的乙酰化，诱导炎症相关ICAM1和VCAM1的表达，并促进单核细胞与ECs的粘附。本课题拟进一步确定miR-200c是否通过靶标SirT1 调控ECs eNOS及NFκB信号通路，明确低切应力通过miR-200c诱导ECs炎症反应，促进动脉粥样硬化的分子机制。研究结果有助于进一步阐明动脉粥样硬化发生的分子和生物力学机制，为动脉粥样硬化相关病变的预防及治疗提供理论依据。

低切应力在动脉粥样硬化血管损伤的发生过程中起重要作用，但其调控机制尚不明确。microRNAs (miRNAs)介导着生理切应力对血管内皮细胞（ECs）功能调控，但迄今针对miR-200c是否参与低切应力对ECs功能的调控尚不明确。我们的研究表明：低切应力诱导miR-200c 的表达，过表达miR-200c可抑制eNOS，KLF2 和 KLF4的表达，促进炎症标志基因VCAM1和ICAM1的表达，从而促进单核细胞粘附到ECs细胞；抑制内源性miR-200c 的表达可以逆转低切应力对eNOS和SIRT1 蛋白表达的抑制作用，同时逆转低切应力诱导的VCAM1和ICAM1的表达。分子机制研究提示，SIRT1和MAPK7 （也称为ERK5）是miR-200c 的靶标；过表达SIRT1 和 eNOS 可部分逆转miR-200c诱导的VCAM-1和ICAM-1的表达；miR-200c可促进NF-κB p65 亚基Lys310位点的乙酰化。进一步的研究表明miR-200c可调控内皮细胞的衰老表型以及线粒体的生物合成。以上数据表明低切应力诱导的miR-200c可能通过SIRT1以及其下游NF-κB 通路调控ECs炎症。我们的研究可为深入理解血流动力学、miRNAs 以及内皮细胞炎症三者的关系提供新见解。在本项目的支持下，我们共发表SCI论著2篇（已标注，IF>4），培养博士研究生2名及硕士研究生3名。

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