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

Acta Pharmacologica Sinica volume 44, pages 1977–1988 (2023)Cite this article

Abstract

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.

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Fig. 1: Screening the new YAP inhibitor thioridazine from an FDA-approved drug library.
Fig. 2: RNA-seq analysis of the transcript profile of thioridazine-treated ECs.
Fig. 3: Thioridazine inhibited disturbed flow-induced endothelial inflammation by restriction of YAP activity.
Fig. 4: Thioridazine regulated YAP activity via suppression of RhoA.
Fig. 5: Oral administration of thioridazine suppressed partial ligation-induced atherogenesis in ApoE−/− mice.
Fig. 6: Chronic thioridazine treatment attenuated high-cholesterol diet-induced atherosclerosis in ApoE−/− mice.
Fig. 7: Schematic overview of repurposing thioridazine for anti-atherosclerotic therapy.

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Acknowledgements

This work was 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. Schematic diagrams were designed by using Figdraw.

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  1. These authors contributed equally: Min-chun Jiang, Huan-yu Ding.

Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

    Min-chun Jiang, Huan-yu Ding, Yu-hong Huang, Chi Wai Lau, Yin Xia, Xiao-qiang Yao & Yu Huang

  2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

    Chak Kwong Cheng, Li Wang & Yu Huang

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Contributions

MCJ and HYD designed the study, performed experiments, and analyzed the data. MCJ wrote the manuscript. YHH, CKC, and CWL participated in part of the experiments. YX, XQY, and LW were involved in regular discussion and revised the manuscript. YH designed the study, analyzed the data, wrote the manuscript, provided grant support, and supervised the study. All authors read and approved the submitted manuscript.

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Correspondence to Yu Huang.

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Jiang, Mc., Ding, Hy., Huang, Yh. et al. Thioridazine protects against disturbed flow-induced atherosclerosis by inhibiting RhoA/YAP-mediated endothelial inflammation. Acta Pharmacol Sin 44, 1977–1988 (2023). https://doi.org/10.1038/s41401-023-01102-w

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