Abstract P2139: The Adiponectin Receptor Agonist ALY688 Prevents Pressure Overload-induced Cardiac Dysfunction And Adverse Cardiac Remodeling

Abstract

Adiponectin has been shown to mediate multiple cardioprotective effects. Since the use of adiponectin protein as a practical therapeutic is associated with multiple challenges, we examined the functional significance of targeting adiponectin signaling with ALY688, a small peptide-based adiponectin mimetic, in a mouse model of cardiac dysfunction caused by left ventricular pressure overload (PO) induced by minimally invasive transverse aortic banding (MTAB). Following daily administration of ALY688 over 5 weeks after induction of PO, echocardiography showed that significantly attenuated PO-induced reduction in ejection fraction and other indices of cardiac function compared with vehicle. ALY688 also significantly reduced cardiac hypertrophic remodeling (heart weight-to-tibia length), cardiomyocyte cross sectional area, and myocardial and circulating levels of serum natriuretic peptide A. ALY688 reduced PO-induced increases in myofibroblasts, and scar tissue collagen content based upon immunofluorescence staining for α-smooth muscle actin and vimentin, scanning electron microscopy, and picrosirius red staining. ALY688 reduced PO-induced myocardial expression of 14 pro-inflammatory genes and circulating IL-12, IL-15, IL-17, and MIP-3α levels. Targeted metabolomics revealed that ALY688 increased myocardial fatty acid oxidation, with increased mobilization of cardiac triacylglycerols and a decrease in sphingomyelin, fatty acids and lysophospholipids. In conclusion, the adiponectin analogue ALY688 is cardioprotective in a preclinical animal model of heart failure and cardiac remodeling, with beneficial metabolic, anti-fibrotic, anti-hypertrophic and anti-inflammatory properties leading to improved cardiac function.