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Updated: Jun 5, 2025
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
The Metabolically Resistant Apelin-17 Analogue LIT01-196 Reduces Cardiac Dysfunction and Remodelling in Heart Failure
Pierre-Emmanuel Girault-Sotias1, Robin Deloux2, Nadia De Mota3
1Laboratory of Central Neuropeptides in the Regulation of Water Balance and Cardiovascular Functions, College de France, CIRB, INSERM U1050/CNRS UMR7241, 75005 Paris, France. Electronic address: https://twitter.com/PiGirault.
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 analogue, LIT01-196 and investigated its effects on cardiac function and remodelling in a murine MI model.
Methods:
The selectivity of LIT01-196 toward the apelin receptor was checked in vitro. Its in vivo 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.
Results:
The in vivo 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.
Conclusions:
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.
