期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 36, 页码 18947-18958出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.739722
关键词
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资金
- National Natural Science Foundation of China [31570784]
- National Institutes of Health [RO1GM067113, RO1CA068377, RO1CA163834, R35CA196878, RO1GM51586, RO1EY022611]
The thromboxane A2 receptor (TP) has been implicated in restenosis after vascular injury, which induces vascular smooth muscle cell (VSMC) migration and proliferation. However, the mechanism for this process is largely unknown. In this study, we report that TP signaling induces VSMC migration and proliferation through activating YAP/TAZ, two major downstream effectors of the Hippo signaling pathway. The TP-specific agonists [1S-[1 alpha,2 alpha(Z),3 beta(1E,3S*),4 alpha]]-7-[3-[3-hydroxy-4-(4-odophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yll-5-hep-tenoic acid (1-BOP) and 9,11-dideoxy-9 alpha,11 alpha-methanoepoxyprosta-5Z,13E-dien-l-oic acid (U-46619) induce YAP/TAZ activation in multiple cell lines, including VSMCs. YAP/TAZ activation induced by I-BOP is blocked by knockout of the receptor TP or knockdown of the downstream G proteins G alpha(12/13). Moreover, Rho inhibition or actin cytoskeleton disruption prevents I-BOP-induced YAP/TAZ activation. Importantly, TP activation promotes DNA synthesis and cell migration in VSMCs in a manner dependent on YAP/TAZ. Taken together, thromboxane A2 signaling activates YAP/TAZ to promote VSMC migration and proliferation, indicating YAP/TAZ as potential therapeutic targets for cardiovascular diseases.
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