Letter | Published:

Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow

Nature volume 540, pages 579582 (22 December 2016) | Download Citation

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This article has been updated

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 stimuli1. 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–Gα13 interaction, 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 MnCl2 reduces plaque formation. Taken together, our results indicate that integrin–Gα13–RhoA–YAP pathway holds promise as a novel drug target against atherosclerosis.

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Change history

  • 21 December 2016

    The acknowledgements sections has been updated.

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Acknowledgements

We thank S. Chien for commenting on the manuscript, and C.-I. Lee and T.-E. Lin for conducting clip experiments. This study was supported by the Hong Kong Research Grants Council (CUHK2/CRF/12G), Natural Science Foundation of China (91339117, 81130002, 31430045), RGC (T12-402/13-N, C7055-14G, CUHK14105814), Croucher Foundation, CUHK Vice Chancellor’s Discretionary Fund, Lui Che Woo Foundation, and the Ministry of Science and Technology, Taiwan (MOST104-2321-B-400-017, MOST104-2320-B-400-002-MY3).

Author information

Affiliations

  1. Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China

    • Li Wang
    • , Jiang-Yun Luo
    • , Xiao Yu Tian
    • , Yuhong Huang
    • , Jian Liu
    • , Dan Deng
    • , Chi Wai Lau
    •  & Yu Huang
  2. School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China

    • Li Wang
    • , Jiang-Yun Luo
    • , Xiao Yu Tian
    • , Yuhong Huang
    • , King-Lun Kingston Mak
    •  & Yu Huang
  3. Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China

    • Bochuan Li
    • , Ding Ai
    •  & Yi Zhu
  4. Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China

    • Bochuan Li
    • , Ding Ai
    •  & Yi Zhu
  5. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan

    • Li-Jing Chen
    •  & Jeng-Jiann Chiu
  6. Department of Surgery, Chinese University of Hong Kong, Hong Kong, China

    • Song Wan
  7. School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China

    • Ka Kui Tong
    •  & Kin Ming Kwan
  8. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China

    • Nanping Wang

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Contributions

L.W. designed the study, conducted most experiments, analysed the data and wrote the manuscript; J.Y.L. helped western blot, contributed ideas and prepared the manuscript. X.Y.T. helped revise the manuscript and provided suggestions for disturbed-flow-induced atherosclerosis; B.L. and D.A. generated EC-specific YAP transgenic mice and performed the in vivo study. Y.H.H. and D.D. performed plasmid construction. L.J.C., J.L. and C.W.L. performed immunohistochemistry and the carotid artery partial ligation surgery. J.J.C. and S.W. helped with atherosclerotic samples and contributed to data analysis. K.L.M., K.K.T. and K.M.K. helped in animal studies. J.J.C. and N.W. provided constructive suggestions in experimental design and helped revise the manuscript. Y.Z. and Y.H. are the leading principal investigators who directed the study and data analysis, and prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yi Zhu or Yu Huang.

Reviewer Information

Nature thanks P. F. Davies, G. Halder and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Figure 1, the original western blot scans and Supplementary Table 1, the information for primers used in the study.

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DOI

https://doi.org/10.1038/nature20602

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