title: Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow.
abstract: The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1), effectors of the Hippo pathway, have been identified as mediators for mechanical stimuli. However, the role of YAP/TAZ in haemodynamics-induced mechanotransduction and pathogenesis of atherosclerosis remains unclear. Here we show that endothelial YAP/TAZ activity is regulated by different patterns of blood flow, and YAP/TAZ inhibition suppresses inflammation and retards atherogenesis. Atheroprone-disturbed flow increases whereas atheroprotective unidirectional shear stress inhibits YAP/TAZ activity. Unidirectional shear stress activates integrin and promotes integrin-Gα13interaction, leading to RhoA inhibition and YAP phosphorylation and suppression. YAP/TAZ inhibition suppresses JNK signalling and downregulates pro-inflammatory genes expression, thereby reducing monocyte attachment and infiltration. In vivo endothelial-specific YAP overexpression exacerbates, while CRISPR/Cas9-mediated Yap knockdown in endothelium retards, plaque formation in ApoE-/-mice. We also show several existing anti-atherosclerotic agents such as statins inhibit YAP/TAZ transactivation. On the other hand, simvastatin fails to suppress constitutively active YAP/TAZ-induced pro-inflammatory gene expression in endothelial cells, indicating that YAP/TAZ inhibition could contribute to the anti-inflammatory effect of simvastatin. Furthermore, activation of integrin by oral administration of MnCl2reduces plaque formation. Taken together, our results indicate that integrin-Gα13-RhoA-YAP pathway holds promise as a novel drug target against atherosclerosis.
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.|School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.|School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jiang-Yun
authors.initials: JY
authors.lastname: Luo
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.|Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Bochuan
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.|School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Li-Jing
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.|School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Deng
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: Department of Surgery, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wan
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.|Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.affiliation: School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: King-Lun Kingston
authors.initials: KK
authors.lastname: Mak
authors.affiliation: School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ka Kui
authors.initials: KK
authors.lastname: Tong
authors.affiliation: School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.|Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.|School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang