Abstract 14321: MURC/Cavin-4, a Muscle-Specific Caveolae-Related Protein, Mediates the Development of Pulmonary Arterial Hypertension Through Enhanced Gα13/p115RhoGEF/RhoA Signaling
[Background] Pulmonary arterial hypertension (PAH) is a progressive disease associated with poor clinical outcome. MURC (muscle-restricted coiled-coil protein)/Cavin-4 is a fourth member of the cavin family which regulates caveolar formation and function together with caveolins. Silencing of caveolin-1 enhances RhoA activity and deficiency of caveolin-1 causes PAH. Since MURC is also expressed in vascular smooth muscle cells (VSMCs), we evaluated the role of MURC in RhoA signaling and the development of PAH.
[Methods and Results] To examine the role of MURC in the pulmonary vascular response to hypoxia, we subjected wild-type (WT) and MURC-knockout (KO) mice to a model of chronic normobaric hypoxia. After hypoxia, WT mice developed marked PAH, whereas MURC-KO mice showed alleviation of PAH with suppressed elevation of right ventricular (RV) systolic pressure, RV hypertrophy, and vascular remodeling. Compared with control VSMCs, MURC-deficient VSMCs had suppressed RhoA activity and reduced proliferation and migration. Overexpression of MURC in VSMCs induced elevation of RhoA activity and promoted proliferation and migration, which were inhibited by a ROCK inhibitor, hydroxyfasudil. MURC was associated with RhoA, especially its active GTP-bound form. MURC was also associated with caveolin-1 and p115RhoGEF, which is activated by Gα13 and promotes RhoA activation, at the plasma membrane in VSMCs. Caveolin-1 had higher affinity for the active form of Gα13 (Gα13-GTP) than the inactive form (Gα13-GDP). The association of caveolin-1 and Gα13-GTP was markedly inhibited by addition of MURC. Furthermore, the association of p115RhoGEF with Gα13-GTP was inhibited by caveolin-1, and the inhibitory action of caveolin-1 was also blocked by MURC. Both of MURC and Gα13 could be associated with the scaffolding domain of caveolin-1, suggesting that MURC has a competitively inhibitory effect on the association of caveolin-1 with Gα13-GTP.
[Conclusions] MURC activates the Gα13/p115RhoGEF/RhoA pathway by competing for the association of caveolin-1 with the active form of Gα13, and promotes the proliferation and migration of VSMCs. Hypoxia-induced PAH and vascular remodeling are alleviated by the absence of MURC with attenuated RhoA signaling in VSMCs.
- © 2012 by American Heart Association, Inc.