Abstract 14809: Murc/cavin-4 Regulates Cardiac Function via β-adrenergic Receptor Signaling

Abstract

Background: Muscle-restricted coiled-coil protein (MURC), also referred to as Cavin-4, is a member of the cavin family, which regulates caveolae function together with caveolins. In cardiomyocytes, caveolin-3, a critical and muscle-specific component of caveolae, regulates caveolar structure and function and forms a complex with MURC/Cavin-4. Caveolin-3 overexpression induces cardiac protection, and caveolin-3 deficiency causes progressive cardiomyopathy. The caveolin-3 scaffolding domain peptide inhibits type 5 adenylyl cyclase (AC5), which is an enzyme to synthesize cAMP and an effector of β-adrenergic receptor (AR) signaling. Mutations in MURC/Cavin-4 have been identified in patients with dilated cardiomyopathy. However, molecular mechanisms of MURC as a caveolar component in cardiac function remain unknown. Methods and results: To assess the role of MURC/Cavin-4 in cardiac function, wild-type (WT) and MURC/Cavin-4-knockout (MURC-KO) mice were subjected to a model of pressure overload induced by transverse aortic constriction (TAC). After TAC, WT mice showed cardiac hypertrophy and heart failure, whereas MURC-KO mice were resistant to pressure overload-induced cardiac hypertrophy and heart failure accompanied by fibrosis. We then focused on β-AR signaling, because β1-AR signaling is one of the essential parts in heart failure. MURC/Cavin-4 was co-localized with β1-AR in cardiomyocytes. Isoproterenol (ISO) treatment induced cardiac hypertrophy with fibrosis in WT mice, while ISO-induced cardiac hypertrophy and fibrosis was markedly attenuated in MURC-KO mice. In cardiomyocytes, MURC/Cavin-4 knockdown suppressed ISO-induced cAMP production, while MURC/Cavin-4 overexpression and caveolin-3 knockdown stimulated cAMP production, indicating that caveolin-3 and MURC/Cavin-4 have opposite effects on cAMP production. MURC/Cavin-4 bound to caveolin-3 and interferes with the association between caveolin-3 and AC5. Moreover, MURC-knockdown suppressed ISO-induced PKA activity and phospholamban phosphorylation. Conclusion: Our findings suggest that MURC/Cavin-4 regulates cardiac function via β-AR signaling.