Abstract

Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes and transient GLP-1 administration improved cardiac function in humans following acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation prior to ischemic myocardial injury remain unclear.

Research Design and Methods: We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pre-treated with the GLP-1R agonist liraglutide.

Results: Male C57BL/6 mice were treated twice daily for 7 d with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide reduced cardiac rupture (12/60 vs. 46/60; P=0.0001), and infarct size (21±2% vs. 29±3%, P=0.02), and improved cardiac output (12.4±0.6 vs. 9.7±0.6; ml/min; P=0.002). Liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart including Akt, GSK3β, PPARβ-δ, Nrf-2, and HO-1. The effects of liraglutide on survival were independent of weight loss. Moreover, liraglutide conferred cardioprotection and survival advantages over metformin, despite equivalent glycemic control, in diabetic mice with experimental MI. The cardioprotective effects of liraglutide remained detectable 4 days following cessation of therapy and may be partly direct, as liraglutide increased cyclic AMP formation and reduced the extent of caspase-3 activation in cardiomyocytes in a GLP-1R-dependent manner in vitro.

Conclusions: These findings demonstrate that GLP-1R activation engages pro-survival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival following MI in vivo.