Pharmacologic Treatment with a Melanocortin Analogue Protects Against Pressure‐Overload Induced Cardiac Hypertrophy

Abstract

PurposeHypertrophic growth of the heart is a consequence of heart ability to adapt to an increased afterload and wall stress. Although left ventricular hypertrophy (LVH) may resolute with adequate therapy, this process increases the amount of irreversible cardiac fibrosis.These morphological and functional changes in the myocardium may manifests as arrhythmias and congestive heart failure (CHF).Melanocortins regulate important physiological functions such as energy balance and blood pressure, but their long‐term effects on cardiac remodeling remain unexplored.In the present study, we investigated whether melanocortins affect physiological or pathologic cardiac growth and function.MethodsFirst, we studied the effects of transgenic melanocortin overexpression (MSH‐OE) on physiological age‐related cardiac growth in 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 pressure‐overload by transverse aortic constriction (TAC) and randomly assigned the mice to receive daily i.p. injections of either vehicle (physiological saline) or MT‐II (0.3 mg/kg) for 6 weeks starting 2 weeks after surgery.ResultsAt the age of 6 months, MSH‐OE mice (n=11) had lower heart weight and smaller myocytes with maintained cardiac function compared to their age‐matched wild‐type littermates (n=15) while no differences in heart weight were noted at the age of 3‐months, indicating that melanocortin overactivity restrains age‐related cardiac growth. Eight weeks of pressure‐overload induced significant left ventricular (LV) hypertrophy with decreased cardiac function in saline‐treated TAC mice (n=15) compared to sham‐operated control mice (n=9).This pathologic cardiac remodeling was attenuated in MT‐II‐treated TAC mice (n=9) (Figure 1. and 2.). Importantly, MT‐II‐treatment did not compromise cardiac function, but tended to maintain LV contractility of TAC mice. Using quantitative NMR scanning to analyze body composition, we demonstrate that MT‐II treatment also prevented the deterioration of body weight development associated with the hypertrophic disease state.MT‐II treatment attenuated also the expression of genes regulating cardiac remodeling related mRNAs such as NppA, NppB, MMP‐2 and Col1a2.ConclusionsAlthough the underlying mechanisms remain largely unclear, these results, for the first time, establish melanocortin signaling as an antihypertrophic regulator and suggest that melanocortin analogues may be potential therapeutic tools for the treatment of cardiac hypertrophy and heart failure.Support or Funding InformationAcademy of Finland, Finnish Cultural Foundation