GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 4; pp. 975 - 983
• Main Authors: Noyan-Ashraf, Mohammad Hossein, Momen, M. Abdul, Ban, Kiwon, Sadi, Al-Muktafi, Zhou, Yu-Qing, Riazi, Ali M., Baggio, Laurie L., Henkelman, R. Mark, Husain, Mansoor, Drucker, Daniel J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2009
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight; Cardiac function; Cardiology. Vascular system; Cardiomegaly - pathology; Cardiomyocytes; Cellular signal transduction; Coronary heart disease; Coronary vessels; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - drug therapy; Diet; Disease Models, Animal; Dosage and administration; Drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - therapeutic use; Glucagon-Like Peptide-1 Receptor; Heart; Heart - anatomy & histology; Heart attack; Heart attacks; Heart failure; Human subjects; Humans; Hypoglycemic agents; Ischemia; Liraglutide; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Infarction - drug therapy; Myocarditis. Cardiomyopathies; Organ Size; Original; Peptides; Receptors, Glucagon - agonists; Research design; Survival analysis; Type 2 diabetes; Veins & arteries; Canada; Endocrinopathy; Myocardial infarction; Vertebrata; Agonist; Mammalia; Mouse; Animal; Diabetes mellitus; Rodentia; Cardiovascular disease; Coronary heart disease; Myocardial disease
• DOI: 10.2337/db08-1193
• ISSN: 0012-1797; 1939-327X

GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes After Experimental Myocardial Infarction in Mice Mohammad Hossein Noyan-Ashraf 1 , M. Abdul Momen 1 , Kiwon Ban 1 , 6 , Al-Muktafi Sadi 1 , Yu-Qing Zhou 2 , Ali M. Riazi 2 , Laurie L. Baggio 3 , R. Mark Henkelman 2 , Mansoor Husain 1 , 4 , 5 , 6 and Daniel J. Drucker 3 , 5 1 Toronto General Hospital, Toronto, Ontario, Canada; 2 Mouse Imaging Centre, Department of Medical Biophysics, Hospital for Sick Children, Toronto, Ontario, Canada; 3 Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; 4 Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada; 5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 6 Department of Physiology, University of Toronto, Toronto, Ontario, Canada. Corresponding author: Daniel J. Drucker, d.drucker{at}utoronto.ca . M.H. and D.J.D. contributed equally to this work. 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, 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 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 28, 2008. Accepted January 9, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.