The Metabolically Resistant Apelin-17 Analogue LIT01-196 Reduces Cardiac Dysfunction and Remodelling in Heart Failure After Myocardial Infarction.

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To protect patients after myocardial infarction (MI) and preserve cardiac function, the development of new therapeutics remains an important issue. Apelin, a neuro-vasoactive peptide, increases aqueous diuresis and cardiac contractility while reducing vascular resistance. However, its invivo half-life is very short. We therefore developed a metabolically resistant apelin-17 analogue, LIT01-196 and investigated its effects on cardiac function and remodelling in a murine MI model. The selectivity of LIT01-196 toward the apelin receptor was checked invitro. Its invivo half-life was assessed in male Swiss mice using radioimmunoassay. After permanent coronary artery ligation to induce MI, mice received subcutaneous administration of LIT01-196 (MI+ LIT01-196, 9 mg/kg/d) or saline (MI+ vehicle) for 4 weeks. Left ventricular (LV) function was assessed using echocardiography and Millar (Houston, TX) catheter, vascular density using immunofluorescence, and cardiac fibrosis using Sirius red staining. Real-time quantitative PCR was used to measure mRNA expression of heart failure (HF) fibrosis biomarkers and sarco/endoplasmic reticulum Ca2+-ATPase-2. The invivo half-life of LIT01-196, a specific and selective apelin receptor agonist, was 2.5 hours. MI+ LIT01-196 showed significantly improved LV function, reduced HF biomarkers, and enhanced cardiac contractility and sarco/endoplasmic reticulum Ca2+-ATPase-2 expression compared with MI+ vehicle. LIT01-196 treatment almost doubled cardiac vascular density and maintained LV wall thickness post MI. It also significantly reduced cardiac fibrosis and fibrosis biomarkers, without decreasing arterial blood pressure. Chronic LIT01-196 treatment post MI improves LV function without decreasing blood pressure, increases cardiac vascular density, and reduces cardiac remodelling. This suggests that apelin receptor activation by LIT01-196 might constitute an original pharmacological approach for HF treatment after MI.