α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor

alpha-Melanocyte-stimulating hormone (alpha-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of alpha-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether alpha-MSH could be involved in pathological cardiac remodeling. We found that alpha-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable alpha-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that MC5-R in cardiomyocytes mediates the anti-hypertrophic signaling of alpha-MSH. Silencing of MC5-R in cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. In conclusion, alpha-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogs of naturally occurring alpha-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure. alpha-Melanocyte-stimulating hormone (alpha-MSH) regulates several physiological functions by interacting with melanocortin receptors (MC1-R-MC5-R). This study shows that alpha-MSH is expressed in the heart and it protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes.alpha-MSH production declines in the failing mouse heart. Pharmacological administration of alpha-MSH alleviates pathological cardiac hypertrophy induced by pressure overload. The protective effects of alpha-MSH are mediated by the melanocortin 5 receptor (MC5-R), which is expressed in mouse and human cardiac myocytes. Silencing MC5-R in cardiomyocytes renders mice susceptible to cardiac hypertrophy and fibrosis after pressure overload. alpha-Melanocyte-stimulating hormone (alpha-MSH) regulates several physiological functions by interacting with melanocortin receptors (MC1-R-MC5-R). This study shows that alpha-MSH is expressed in the heart and it protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes.