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


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.
Noyan-Ashraf
Mohammad Hossein
MH
Toronto General Hospital, Toronto, Ontario, Canada.
Momen
M Abdul
MA
Ban
Kiwon
K
Sadi
Al-Muktafi
AM
Zhou
Yu-Qing
YQ
Riazi
Ali M
AM
Baggio
Laurie L
LL
Henkelman
R Mark
RM
Husain
Mansoor
M
Drucker
Daniel J
DJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D006332:Cardiomegaly / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000188:drug therapy; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006321:Heart / Q000033:anatomy & histology; D006801:Humans; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy*; D009929:Organ Size; D018027:Receptors, Glucagon / Q000819:agonists*
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1