Abstract 12905: Deficiency of MURC/Cavin-4 Alleviates Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is a progressive disease associated with a poor prognosis. The Rho/ROCK pathway has been suggested to be associated with PAH. MURC/Cavin-4, a fourth member of the cavin family which regulates caveolar formation and function together with caveolins, regulates the Rho/ROCK pathway in cardiomyocytes. Deficiency of caveolin-1 (Cav1) enhances RhoA activity and causes PAH. Mutations in Cav1 are also associated with PAH. Although MURC is expressed in vascular smooth muscle cells (VSMCs), the role of MURC in RhoA signaling in VSMCs and the development of PAH remains unknown.
Methods and Results: To examine the role of MURC in PAH, we subjected wild-type (WT) and MURC-knockout (MURC-/-) mice to a model of chronic normobaric hypoxia. MURC-/- mice exhibited attenuation of hypoxia-induced PAH and vascular remodeling compared with WT mice. We then examined the role of MURC in VSMCs. VSMCs isolated from MURC-/- mice had reduced RhoA activity, proliferation and migration, while MURC overexpression in VSMCs enhanced them. MURC-induced proliferation and migration were inhibited by a ROCK inhibitor. We further examined the relationship between MURC and Cav1 on RhoA signaling. Overexpression of Cav1 suppressed RhoA activity in VSMCs 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 was reversed by MURC overexpression. MURC 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 and Gα13 were associated with the scaffolding domain of Cav1. These findings suggest that MURC competitively inhibits the interaction of Cav1 with Gα13, thereby activating RhoA signaling.
Conclusions: Absence of MURC attenuates PAH with suppressed vascular remodeling. MURC regulates proliferation and migration through the Rho/ROCK pathway in VSMCs. MURC is associated with Cav1, which induces Gα13-mediated activation of Rho signaling. Our findings provide novel insight into the mechanisms of caveola-mediated Rho/ROCK signaling in the development of PAH.
- © 2013 by American Heart Association, Inc.