Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras and CaMKII Signaling
Background—Cardiac hypertrophy is an early hallmark during the clinical course of heart failure (HF) 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 HF. Four weeks after transverse aortic constriction (TAC), Carabin deficient (Carabin-/-) mice developed exaggerated cardiac hypertrophy and displayed a strong decrease in fractional shortening (FS) (14.6 ± 1.6 % versus 27.6 ± 1.4% in wild type + TAC mice, P <0.0001). Conversely, compensation of Carabin loss through a cardiotropic adeno-associated viral vector encoding Carabin prevented TAC-induced cardiac hypertrophy with preserved FS (39.9 ± 1.2 % versus 25.9 ± 2.6% in control + TAC 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 (CaN) interacting site and Ras/Rab GTPase activating protein (GAP) domain functions as an endogenous inhibitor of CaN and Ras/extracellular signal-regulated kinase prohypertrophic signaling. Moreover, Carabin reduced Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and prevented nuclear export of histone deacetylase 4 following adrenergic stimulation or myocardial pressure overload. Finally, we showed that Carabin Ras-GAP domain and CaN interacting domain were both involved in the anti-hypertrophic action of Carabin.
Conclusions—Our study identifies Carabin as a negative regulator of key prohypertrophic signaling molecules, CaN, Ras, and CaMKII and implicates Carabin in the development of cardiac hypertrophy and failure.
- Received April 18, 2014.
- Revision received October 28, 2014.
- Accepted November 3, 2014.