A Novel Peptoid Hybrid of Alpha-Calcitonin Gene-Related Peptide (α-CGRP) Ameliorates Cardiac Remodeling in Pressure Overload-Induced Heart Failure.

α-CGRP (alpha-calcitonin gene-related peptide) is a vasoactive and anti-inflammatory neuropeptide that is cardioprotective in transverse aortic constriction (TAC)-induced pressure overload heart failure (HF) models. Our previous investigations established that a peptoid modification of α-CGRP, termed NMEG-CGRP, prevented left ventricular (LV) dysfunction and remodeling when administered subcutaneously every other day for 28 days, starting two days post-TAC surgery (termed prevention study). Here, we determined whether NMEG-CGRP would be cardioprotective when administered after the development of LV dysfunction secondary to TAC surgery (termed treatment study). Starting 15 days post-sham or TAC surgery, we administered NMEG-CGRP (3.6 mg/kg/mouse) subcutaneously every other day for 28 days in mice assigned to treatment groups. In vivo assessments included weekly electrocardiography to evaluate cardiac function and blood sampling for immunophenotyping. On Day 45, mice were euthanized, and hearts were collected for gross, histological, and biochemical analyses. Compared to sham-operated mice, TAC mice exhibited decreased LV ejection fraction and increased hypertrophy, dilation, fibrosis, apoptosis, and oxidative stress. In contrast, TAC mice treated with NMEG-CGRP demonstrated significant improvements in cardiac function and cellular and biochemical parameters when compared to TAC mice. These findings demonstrate the therapeutic potential of NMEG-CGRP in the treatment of established cardiovascular dysfunction and its progression in pressure overload-induced HF.