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OBJECTIVE- Glucagon-like peptide-1 receptor (GLP-IR) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-IR activation before ischemic myocardial injury remain unclear.
RESEARCH DESIGN AND METHODS- We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-IR agonist liraglutide.
RESULTS- Male C57BIV6 mice were treated twice daily for days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. glutide reduced cardiac rupture (12 of 60 versus 46 of 60; P = 0.0001) and infarct size (21 ± 2% versus 29 ± 3%, P = 0.02) and improved cardiac output (12.4 ± 0.6 versus 9.7 ± 0.6 ml/min; P = 0.002). Liraglutide also modulated the expression and activity 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, spite equivalent glycemic control, in diabetic mice with mental MI. The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct, because liraglutide increased cyclic AMP formation reduced the extent of caspase-3 activation in cardiomyocytes in a GLP- IR- dependent manner in vitro.
CONCLUSIONS-These findings demonstrate that GLP-IR tivation engages prosurvival pathways in the normal and mouse heart, leading to improved outcomes and enhanced survival after MI in vivo. Diabetes 58:975-983, 2009
The protection against ischemic damage provided by cycling periods of ischemia and reperfusion, that is, ischemic preconditioning (IP), may last for hours or even days (1). Although the molecular basis of ischemic preconditioning is complex and incompletely understood, there is active interest in the development of therapeutic interventions that protect the myocardium against ischemic injury.
Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family (2), exerts favorable actions on cardiovascular function in both preclinical and clinical studies. A functional GLP-I receptor (GLP-IR) is expressed in the heart (3), and GLP-IR agonists directly activate cardiomyocyte signaling pathways (4). Because the GLP-IR is also expressed in the endocrine pancreas, GLP-1 may regulate cardiac function indirectly through metabolic control of glucose, insulin, glucagon,...