Pharmacological treatment with a melanocortin analogue protects against pressure‐overload‐induced cardiac hypertrophy

Abstract

Melanocortins regulate important physiological functions such as energy balance and blood pressure, but their long‐term effects on cardiac remodeling remain unexplored. Therefore, using gain‐of‐function models of melanocortin activity, we investigated whether melanocortins affect physiological or pathological cardiac growth. First, we studied the effects of transgenic melanocortin overexpression (MSH‐OE) on physiological age‐related cardiac growth. 6‐month‐old MSH‐OE mice had lower heart weight with maintained cardiac function compared to age‐matched wild‐type mice. Second, we examined the effects of a stable melanocortin analogue (MT‐II) on pressure‐overload‐induced cardiac hypertrophy. We subjected 8‐week‐old C57Bl/6N mice to transverse aortic constriction (TAC) and treated them with either saline or MT‐II (0.3 mg/kg/day for 6 weeks, i.p.). Saline‐treated TAC mice displayed significant increases in ventricular weight and LV posterior wall thickness, and impaired systolic function compared to sham‐operated control mice. This pathological cardiac remodeling was attenuated in MT‐II‐treated TAC mice. Importantly, MT‐II‐treatment did not compromise cardiac function, but tended to rather improve LV contractility in TAC mice. In conclusion, these results establish melanocortin signaling as an antihypertrophic regulator in physiological and pathological cardiac remodeling.