Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Nat Commun. 2016 Aug 22;7:12417. doi: 10.1038/ncomms12417.
Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling.
新出现的证据表明，窖蛋白-1（Cav1）与肺动脉高压有关。MURC（也称为Cavin-4）是 Cavin 家族的一员，它调节小窝的形成，并与窖蛋白一起发挥作用。在这里，我们表明缺氧会增加小鼠肺部的 Murc mRNA 表达，而 Murc 基因敲除小鼠表现出缺氧诱导的肺动脉高压（PH）的减弱，同时肺部的 ROCK 活性降低。缺乏平滑肌中 Murc 的条件性基因敲除小鼠也能抵抗缺氧诱导的 PH。MURC 通过 Rho/ROCK 信号通路调节肺动脉平滑肌细胞（PASMC）的增殖和迁移。Cav1 抑制 PASMC 中的 RhoA 活性，而 Murc 可逆转这种抑制作用。MURC 与 Cav1 结合并抑制 Cav1 与 Gα13 活性形式的结合，从而促进 Gα13 活性形式与 p115RhoGEF 的结合。这些结果表明，MURC 通过调节 Rho/ROCK 信号通路在 PH 的发展中具有功能。
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