Thioridazine protects against disturbed flow-induced atherosclerosis by inhibiting RhoA/YAP-mediated endothelial inflammation  

作　　者：Min-chun Jiang Huan-yu Ding Yu-hong Huang Chak Kwong Cheng Chi Wai Lau Yin Xia Xiao-qiang Yao Li Wang Yu Huang 

机构地区：[1]School of Biomedical Sciences,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong,China [2]Department of Biomedical Sciences,City University of Hong Kong,Hong Kong,China

出　　处：《Acta Pharmacologica Sinica》2023年第10期1977-1988,共12页中国药理学报（英文版）

基　　金：supported by Hong Kong Research Grants Council(SRFS2021-4S04,14112919,14164817,14109720);Hong Kong PhD Fellowship Scheme,and Health and Medical Research Fund(07181286)of China.

摘　　要：Atherosclerotic diseases remain the leading cause of adult mortality and impose heavy burdens on health systems globally. Our previous study found that disturbed flow enhanced YAP activity to provoke endothelial activation and atherosclerosis, and targeting YAP alleviated endothelial inflammation and atherogenesis. Therefore, we established a luciferase reporter assay-based drug screening platform to seek out new YAP inhibitors for anti-atherosclerotic treatment. By screening the FDA-approved drug library, we identified that an anti-psychotic drug thioridazine markedly suppressed YAP activity in human endothelial cells. Thioridazine inhibited disturbed flow-induced endothelial inflammatory response in vivo and in vitro. We verified that the anti-inflammatory effects of thioridazine were mediated by inhibition of YAP. Thioridazine regulated YAP activity via restraining RhoA. Moreover, administration of thioridazine attenuated partial carotid ligation- and western diet-induced atherosclerosis in two mouse models. Overall, this work opens up the possibility of repurposing thioridazine for intervention of atherosclerotic diseases. This study also shed light on the underlying mechanisms that thioridazine inhibited endothelial activation and atherogenesis via repression of RhoA-YAP axis. As a new YAP inhibitor, thioridazine might need further investigation and development for the treatment of atherosclerotic diseases in clinical practice.

关 键 词：ATHEROSCLEROSIS ENDOTHELIUM INFLAMMATION disturbed flow Yes-associated protein THIORIDAZINE 

分 类 号：R965[医药卫生—药理学]