Abstract 15887: MURC/cavin-4 Functions as a Negative Regulator of Caveolin-3 in Tte Development of Heart Failure
Background: Muscle-restricted coiled-coil protein (MURC)/cavin-4 is a novel member of the cavin family that regulates caveolae function. Caveolae formation and function are also regulated by caveolin-3 in cardiomyocytes (CMs). Overexpression of caveolin-3 induces cardiac protection, and loss of caveolin-3 causes progressive cardiomyopathy. Mutations in MURC have been identified in patients with dilated cardiomyopathy. However, the role of MURC as a caveolar component protein remains unknown.
Methods and Results: To assess the role of MURC in the development of heart failure, MURC-knockout (KO) and wild-type (WT) mice were subjected to pressure overload by transverse aortic constriction (TAC). After TAC, WT mice developed overt heart failure and eccentric cardiac hypertrophy, whereas MURC-KO mice showed preserved cardiac function accompanied by attenuated cardiac hypertrophy. We then focused on β-adrenergic receptor (AR) signaling, because MURC was colocalized and associated with β1-AR. Isoproterenol (ISO)-induced cardiac hypertrophy and fibrosis were significantly attenuated in MURC-KO mice compared with WT mice. Knockdown of MURC suppressed ISO-induced cAMP production in CMs, whereas overexpression of MURC as well as knockdown of caveolin-3 stimulated cAMP production. MURC was also colocalized and associated with caveolin-3 at the plasma membrane of CMs, suggesting an inhibitory interaction of MURC with caveolin-3 for cAMP production in β-adrenergic signaling. To explore the functional role of MURC localization to caveolae, we made a MURC mutant lacking the coiled-coil domain (MURCΔCC), which was primarily localized to the cytoplasm. MURCΔCC impaired membrane localization of caveolin-3, resulting in increased cAMP levels in CMs compared with MURC. Transgenic mice expressing cardiac-specific MURCΔCC exhibited progressive cardiac dysfunction and intraventricular conduction delay accompanied by impaired membrane localization of SCN5A, which was associated with caveolin-3.
Conclusion: MURC functions as a negative regulator of caveolin-3 at caveolae and modulates localization of caveolin-3 in CMs. MURC regulates cardiac function through modulation of caveolin-3 function and localization in the cAMP signaling pathway.
- © 2012 by American Heart Association, Inc.