Abstract
The Glp-1 analog, liraglutide (Lir), has been shown to reduce infarct size and improve cardiac function after myocardial ischemia in rodents with or without diabetes. However, the effect of Lir on angiotensin II (AngII) and pressure overload induced cardiac hypertrophy in nondiabetic mice and the underlying mechanisms are unclear. The aim of this study was to investigate the effect of Lir on cardiac hypertrophy induced by AngII infusion and pressure overload and to explore its possible mechanism. Mice were subjected to AngII as well as thoracic aorta coarctation (TAC) to induce a cardiac hypertrophy model. Mice were daily injected with either liraglutide or saline for 2 weeks after AngII infusion. Mice were also subjected to either liraglutide or saline for 25 days after TAC surgery. Neonatal rat cardiomyocytes and human AC cell lines were stimulated with AngII to induce a cardiomyocytes hypertrophy model. The results indicated Lir significantly inhibited cardiac hypertrophy and fibrosis and improved cardiac function in both the AngII and pressure overload induced model. The in vitro study showed that Lir inhibits AngII induced cell hypertrophy. Mechanistically, Lir directly suppressing the activation of PI3K/Akt1 and stimulated AMPKα signaling pathways in cardiomyocytes, which was confirmed by use of an mTOR activator (MHY1485), overexpression of constitutively active Akt, and the knockdown of AMPKa2 expression. Moreover, the protective effects of Lir were lost in AMPKa2 knockout mice. Taken together, Lir inhibits AngII and pressure overload induced cardiac remodeling via regulating PI3K/Akt1 and AMPKα signaling.