The metabolically resistant apelin-17 analog LIT01-196 reduces cardiac dysfunction and remodeling in heart failure after myocardial infarction.

Background: 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 in vivo half-life is very short. We therefore developed a metabolically resistant apelin-17 analog, LIT01-196 and investigated its effects on cardiac function and remodeling in a murine MI model.

Methods: The selectivity of LIT01-196 towards ApelinR was checked in vitro. Its in vivo half-life was assessed in male Swiss mice by radioimmunoassay. After permanent coronary artery ligation to induce MI, mice received subcutaneous administration of LIT01-196 (MI+LIT01-196, 9 mg/kg/day) or saline (MI+Vehicle) for 4 weeks. LV function was assessed using echocardiography and Millar catheter, vascular density by immunofluorescence and cardiac fibrosis by Sirius red staining. Real-time quantitative PCR measured mRNA expression of HF and fibrosis biomarkers and SERCA2.

Results: The in vivo half-life of LIT01-196, a specific and selective ApelinR agonist, was two and a half hours. MI+LIT01-196 mice showed significantly improved LV function, reduced HF biomarkers and enhanced cardiac contractility and SERCA2 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.

Conclusions: Chronic LIT01-196 treatment post-MI improves LV function without decreasing blood pressure, increases cardiac vascular density and reduces cardiac remodeling. This suggests that Apelin-R activation by LIT01-196, may constitute an original pharmacological approach for HF treatment after MI.