GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.

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 after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R 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-1R agonist liraglutide.

RESULTS:

Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide 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 of cardioprotective genes in the mouse heart, including Akt, GSK3beta, PPARbeta-delta, 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 after cessation of therapy and may be partly direct, because 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 prosurvival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival after MI in vivo.

• Authors: Mohammad Hossein Noyan-Ashraf, M Abdul Momen, Kiwon Ban, Al-Muktafi Sadi, Yu-Qing Zhou, Ali M Riazi, Laurie L Baggio, R Mark Henkelman, Mansoor Husain, Daniel J Drucker
• Journal: Diabetes (Diabetes) Vol. 58 Issue 4 Pg. 975-83 (Apr 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19151200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• GLP1R protein, human
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Receptors, Glucagon
• Liraglutide
• Glucagon-Like Peptide 1

Topics

• Animals
• Blood Glucose (metabolism)
• Body Weight
• Cardiomegaly (pathology)
• Diabetes Mellitus, Type 2 (drug therapy)
• Diabetic Angiopathies (drug therapy)
• Disease Models, Animal
• Glucagon-Like Peptide 1 (analogs & derivatives, therapeutic use)
• Glucagon-Like Peptide-1 Receptor
• Heart (anatomy & histology)
• Humans
• Liraglutide
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (drug therapy)
• Organ Size
• Receptors, Glucagon (agonists)