Abstract 12359: Thioridazine Suppresses Endothelial Inflammation and Atherogenesis Through Inhibition of Yap-jnk Signaling Axis

Abstract

Introduction: Atherosclerosis is a critical public health issue as cardiovascular disease has been on the rise globally for decades. Our previous study found that YAP plays a critical role in endothelial inflammation and atherosclerosis, indicating that YAP is a promising therapeutic target against atherosclerotic vascular diseases. Therefore, we established the drug screening platform, aiming to seek new YAP inhibitors through repurposing FDA-approved drugs. Methods and Results: Drug screening was initially performed by luciferase reporter gene assay. We found that the anti-psychotic drug thioridazine can significantly inhibit the YAP/TAZ activity in human endothelial cells. Thioridazine downregulated the mRNA levels of YAP/TAZ target genes (ANKRD1, CTGF, CYR61) in endothelial cells. Thioridazine also increased the phosphorylation of YAP and inhibited the nuclear translocation of YAP in endothelial cells. Thioridazine suppressed endothelial inflammation, as demonstrated by downregulation of JNK phosphorylation, activity of JNK effector AP-1 as well as mRNA expression of pro-inflammatory markers including JNK target genes. Moreover, we observed that oral administration of thioridazine alleviated the formation of atherosclerotic plaques in ApoE -/- mice on a western diet. Conclusion: Overall, the FDA-approved clinical drug, thioridazine suppresses endothelial inflammation and atherogenesis through inhibition of YAP-JNK signaling pathway. As a novel YAP inhibitor, thioridazine might need further investigation and development for potential use of treating atherosclerotic vascular disease.