C ardiac hypertrophy, the compensatory response of the heart to stress, is characterized by nonmitotic growth, the addition of new sarcomeres, and fetal gene expression. 1 However, prolonged hypertrophy of the myocardium can progress to heart failure (HF), a leading cause of morbidity and mortality, often associated with sudden cardiac death.
2-4Thus, understanding the signaling mechanisms that regulate pathological cardiac hypertrophy may lead to a better treatment for patients with HF.The hypertrophic growth of the myocardium is typically initiated by signal transduction pathways in response to Background-Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood. Methods and Results-Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure. Four weeks after transverse aortic constriction, Carabin-deficient (Carabin −/− ) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (14.6±1.6% versus 27.6±1.4% in wild type plus transverse aortic constriction mice; P<0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented transverse aortic constrictioninduced cardiac hypertrophy with preserved fractional shortening (39.9±1.2% versus 25.9±2.6% in control plus transverse aortic constriction mice; P<0.0001). Carabin also conferred protection against adrenergic receptor-induced hypertrophy in isolated cardiomyocytes. Mechanistically, Carabin carries out a tripartite suppressive function. Indeed, Carabin, through its calcineurin-interacting site and Ras/Rab GTPase-activating protein domain, functions as an endogenous inhibitor of calcineurin and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca 2+ / calmodulin-dependent protein kinase II activation and prevented nuclear export of histone deacetylase 4 after adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GTPase-activating protein domain and calcineurin-interacting domain were both involved in the antihypertrophic action of Carabin. Conclusions-Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, calcineurin, Ras, and Ca
2+/calmodulin-dependent protein kinase II and implicates Carabin in the development of cardiac hypertrophy and failure. (Circulation. 2015;131:390-400.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.