Abstract 13497: Murc/Cavin-4 Regulates Cardiac Function Through Modulation of Caveolin-3 Function in β-adrenergic Receptor Signaling
Background: Muscle-restricted coiled-coil protein (MURC)/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/Cavin-4 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 colocalized 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/Cavin-4 knockdown suppressed ISO-induced protein kinase A activity.
Conclusion: Our findings suggest that MURC/Cavin-4 functions as a negative regulator of caveolin-3 for AC5 and regulates cardiac function through modulation of β-AR signaling.
Author Disclosures: T. Hamaoka: None. T. Ogata: None. D. Naito: None. N. Nakanishi: None. K. Miyagawa: None. N. Maruyama: None. T. Kasahara: None. T. Shirayama: None. T. Ueyama: None.
- © 2014 by American Heart Association, Inc.