Abstract 13756: Smooth Muscle-specific Deletion of MURC/Cavin-4 Alleviates Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is a progressive disease associated with a poor prognosis. Caveolin-1 (Cav1) deficiency causes PAH in mice and mutations in gene are identified in patients with PAH. MURC/Cavin-4, a member of the cavin family which regulates caveolar formation and function together with caveolins, regulates Rho/ROCK signaling in cardiomyocytes. Rho/ROCK signaling has been suggested to be involved in PAH. However, roles of MURC/Cavin-4 in the development of PAH remain unknown.
Methods and Results: MURC/Cavin-4-floxed (MURCfl/fl) mice and smooth muscle-specific MURC/Cavin-4 (SM22Cre+MURCfl/fl) conditional knockout (cKO) mice were subjected to chronic normobaric hypoxia. cKO mice exhibited attenuation of hypoxia-induced PAH and vascular remodeling compared with MURCfl/fl mice. We then examined roles of MURC/Cavin-4 in pulmonary arterial smooth muscle cells (PASMCs). MURC/Cavin-4 knockdown in human PASMCs (hPASMCs) reduced RhoA activity, proliferation and migration, while MURC/Cavin-4 overexpression enhanced them. MURC/Cavin-4-induced proliferation and migration in hPASMCs were suppressed by a ROCK inhibitor, and MURC/Cavin-4-induced RhoA activation was inhibited by dominant-negative p115RhoGEF. Cav1 overexpression suppressed RhoA activity in hPASMCs, and Cav1 was associated with the active form of Gα13 (Gα13-GTP), suggesting that the association of Cav1 with Gα13 inhibits Gα13-mediated RhoA signaling. Cav1-mediated suppression of RhoA activity in hPASMCs was reversed by MURC/Cavin-4 overexpression. MURC/Cavin-4 bound to Cav1 and decreased the binding of Cav1 to Gα13-GTP, which facilitated the association of Gα13-GTP with p115RhoGEF. Furthermore, both of MURC/Cavin-4 and Gα13 were associated with the scaffolding domain of Cav1. These findings suggest that MURC/Cavin-4 competitively inhibits the interaction of Cav1 with Gα13, thereby activating RhoA signaling.
Conclusions: MURC/Cavin-4 deficiency in SMCs attenuates PAH with suppressed vascular remodeling. MURC/Cavin-4 is associated with Cav1, which regulates Gα13-mediated activation of Rho signaling. Our findings provide novel insight into mechanisms of caveola-mediated Rho/ROCK signaling in the development of PAH.
Author Disclosures: N. Nakanishi: None. T. Ogata: None. K. Miyagawa: None. T. Hamaoka: None. N. Maruyama: None. T. Kasahara: None. T. Ueyama: None.
- © 2014 by American Heart Association, Inc.