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

Nature volume 540, pages 579–582 (2016)Cite this article

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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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Figure 1: Haemodynamics regulates YAP phosphorylation, subcellular localization, downstream gene expression and reporter gene activity in ECs.
Figure 2: Integrin inhibits YAP/TAZ activity through Gα13-mediated RhoA inhibition.
Figure 3: YAP/TAZ activation induces adhesion molecule expression through increasing JNK activity.
Figure 4: Suppression of YAP/TAZ activity retards atherogenesis.

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  • 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).

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Authors and 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.

Corresponding authors

Correspondence to Yi Zhu or Yu Huang.

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The authors declare no competing financial interests.

Additional information

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.

Extended data figures and tables

Extended Data Figure 1 USS and disturbed flow oppositely regulate YAP/TAZ activity.

a, Immunoblotting showing USS induces YAP phosphorylation in human aortic ECs. b, Summarized data for USS-induced YAP nuclear exportation (n = 5; *P < 0.05 by two-tailed unpaired t-test). c, TAZ is decreased in nuclear fractions and increased in cytoplasmic fractions in HUVECs exposed to USS for 6 h. TAZ expression was detected by immunoblotting after cell fractionation. d, Disturbed flow suppresses YAP phosphorylation in human aortic ECs. e, Immunoblotting showing disturbed flow increases CTGF expression in HUVECs. All immunoblotting experiments were repeated three times and the representative results are shown. f, g, YAP/TAZ knockdown attenuates gene expression of disturbed-flow-induced (f) CTGF and (g) CYR61 (n = 3; *P < 0.05 by two-tailed unpaired t-test). NS, not significant. h, Summarized data for en face staining of relative nuclear YAP level in mouse aorta (nTA = 6, nAA, inner = 3, nAA, outer = 3; *P < 0.05 by two-tailed unpaired t-test).

Source data

Extended Data Figure 2 USS inhibits YAP/TAZ through integrin–Gα13–RhoA pathway.

a, MnCl2 (0.5 mM) promotes YAP phosphorylation shown by immunoblotting. b, MnCl2 reduces nuclear YAP/TAZ levels in HUVECs. c, Gα13 inhibiting peptide mSRI reverses MnCl2-induced YAP/TAZ reporter (8×GTIIC-luc) gene activity (n = 3; *P < 0.05 by two-tailed unpaired t-test). d, RGD-containing peptide GRGDSP downregulates YAP/TAZ downstream target gene expression (n = 3; *P < 0.05 by two-tailed unpaired t-test). e, f, Pro32pro33 mutation in integrin β3 inhibits YAP/TAZ transactivation in HUVECs, as verified by suppressed (e) expression of YAP/TAZ target genes and (f) YAP/TAZ reporter gene activity (n = 3; *P < 0.05 by two-tailed unpaired t-test). g, Gα13 or integrin β3 knockdown reverses MnCl2-induced YAP/TAZ nuclear exportation in HUVECs. h, Gα13 knockdown reverses RGD-containing peptide-mediated CTGF and CYR61 suppression in HUVECs (n = 3; *P < 0.05 by two-tailed unpaired t-test). i, Gα13 inhibiting peptide mSRI and mP6 reverse MnCl2-induced (5 min) pYAP but not total YAP expression in HUVECs. The experiments were repeated at least three times and the representative results are shown.

Source data

Extended Data Figure 3 YAP/TAZ activation increases JNK activity.

a, Heatmap for mRNA sequencing results showing CA-YAP/TAZ promotes expression of pro-inflammatory genes. b, CA-YAP/TAZ increases the promoter activity of adhesion molecules in HUVECs (n = 4; *P < 0.05 by two-tailed unpaired t-test). c, Summarized data for CA-YAP/TAZ overexpression increases monocyte attachment to HUVECs (n = 4; *P < 0.05 by two-tailed unpaired t-test). d, e, Immunoblotting showing JNK phosphorylation in HUVECs exposed to (d) USS or (e) disturbed flow for different durations. Experiments were repeated three times and the representative results are shown. f, YAP/TAZ knockdown suppresses basal and PMA-induced JNK phosphorylation in HUVECs. g, Overexpression of dominant-negative YAP (YAP S94A) inhibits PMA-induced AP-1 reporter gene activity (n = 3; *P < 0.05 by two-tailed unpaired t-test). h, CA-YAP/TAZ increases AP-1 reporter gene activity in HUVECs (n = 4; *P < 0.05 by two-tailed unpaired t-test), and PMA was used as positive control for monitoring AP-1 activity.

Source data

Extended Data Figure 4 EC-specific overexpression of YAP accelerates plaque formation.

a, The generation of Cre-mediated EC-specific YAP overexpression transgenic mice. b, En face staining showing increased YAP expression in endothelial cells of the Tie2Cre/+;Yap-COEtg/+;ApoE−/− (n = 10). c, Summarized data for EC-specific YAP overexpression-increased JNK phosphorylation (n = 10; *P < 0.05 by two-tailed unpaired t-test). d, EC-specific YAP overexpression increases macrophage content in the atherosclerotic plaques from aortic root (n = 10; *P < 0.05 by two-tailed unpaired t-test). e, f, EC-specific YAP overexpression does not affect serum levels of (e) cholesterol or (f) triglycerides (n = 10; *P < 0.05 by two-tailed unpaired t-test).

Source data

Extended Data Figure 5 Inhibiting TAZ activity by shRNA or MnCl2 administration delays atherogenesis and is independent of lipid metabolism, while activating YAP/TAZ by AAV-mediated CA-YAP/TAZ overexpression accelerates atherosclerotic plaque formation.

a, Immunoblotting showing adenovirus-mediated TAZ shRNA suppressed TAZ expression level. b, TAZ knockdown delayed Western-diet-induced plaque formation in ApoE−/− mice, n = 5; *P < 0.05 by two-tailed unpaired t-test. c, TAZ knockdown-suppressed plaque formation in ApoE−/− mice is not due to change in lipid profile. Data are expressed as mean ± s.e.m., n = 5; *P < 0.05 by two-tailed unpaired t-test. d, Immunoblotting showing increased YAP expression in mice injected with AAV expressing CA-YAP/TAZ. e, f, Oil Red O staining (e) and summarized data (f) for CA-YAP/TAZ-induced exacerbation of plaque formation; n = 5, *P < 0.05 by two-tailed unpaired t-test. g. AAV-mediated CA-YAP/TAZ overexpression does not affect lipid profile in ApoE−/− mice. h, i, Oral administration of MnCl2 does not affect (h) lipid profile or (i) SOD activity in liver. Data are expressed as mean ± s.e.m., n = 5; *P < 0.05 by two-tailed unpaired t-test.

Source data

Extended Data Figure 6 Summary of western blotting data.

a, Endothelium removal reduces YAP level in mouse aorta. b, USS increases YAP phosphorylation. c, Disturbed flow reduces YAP phosphorylation. d, Thoracic aorta expresses higher levels of pYAP than aortic arch. e, Overexpression loss-of-function mutation of integrin β3 (β3Δcyto) suppresses USS-induced pYAP. f, RGD-containing peptide GRGDSP induces pYAP. g, Gα13 or integrin β3 knockdown reverses MnCl2-induced pYAP. h, Integrin gain-of-function mutation Pro32Pro33 increases pYAP. i, Constitutively activated RhoA (CA-RhoA) reverses USS-induced pYAP. Data: n = 6 for a and n = 3 for other figures; *P < 0.05 by two-tailed unpaired t-test.

Source data

Extended Data Figure 7 Summary of western blotting data.

a, CA-RhoA reverses MnCl2-induced pYAP. b, Gα13 knockdown reverses USS-induced pYAP. c, Gα13 inhibitor SRI reverses USS-induced pYAP. d–h, Immunoblotting detection of (d) pYAP, (e) YAP, (f) TAZ, (g) Gα13 and (h) integrin β3 levels. i, YAP knockdown by the CRISPR-Cas9 in vivo genome editing system. Data: n = 3 for a–c, n = 5 for d–i; *P < 0.05 by two-tailed unpaired t-test.

Source data

Extended Data Table 1 Drugs and concentrations used for the YAP/TAZ inhibition test
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This file contains Supplementary Figure 1, the original western blot scans and Supplementary Table 1, the information for primers used in the study. (PDF 1477 kb)

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Wang, L., Luo, JY., Li, B. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016). https://doi.org/10.1038/nature20602

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