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PRE-CLINICAL RESEARCH

Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

Leo Timmers, MD, PhD^_*,,_*, José P.S. Henriques, MD, Dominique P.V. de Kleijn, PhD^_*,||, J. Hans DeVries, MD, PhD, Hans Kemperman, PhD, Paul Steendijk, PhD^¶, Cees W.J. Verlaan, BSc^_*, Marjolein Kerver, MSc^_*, Jan J. Piek, MD, PhD, FACC, Pieter A. Doevendans, MD, PhD^_*, Gerard Pasterkamp, MD, PhD^_* and Imo E. Hoefer, MD, PhD^_*

^_* Department of Cardiology, University of Medical Center Utrecht, UMC Utrecht, the Netherlands
Department of Clinical Chemistry and Hematology, University of Medical Center Utrecht, Utrecht, the Netherlands
Department of Cardiology, Academic Medical Center, AMC Amsterdam, the Netherlands
Department of Internal Medicine, Academic Medical Center, Amsterdam, Amsterdam, the Netherlands
^|| Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
^¶ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

Manuscript received June 23, 2008; revised manuscript received October 20, 2008, accepted October 20, 2008.

^_* Reprint requests and correspondence: Dr. Leo Timmers, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Room number G02.523, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands (Email: l.timmers{at}umcutrecht.nl).

Objectives: This study sought to examine whether exenatide is capable of reducing myocardial infarct size.

Background: Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI).

Methods: Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress.

Results: Exenatide reduced myocardial infarct size (32.7 ± 6.4% vs. 53.6 ± 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 ± 6.3% vs. 8.1 ± 1.9%, p < 0.001; myocardial stiffness: 0.12 ± 0.06 mm Hg/ml vs. 0.22 ± 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels.

Conclusions: These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Key Words: exenatide • glucagon-like peptide 1 • myocardial infarction • reperfusion

Abbreviations and Acronyms   AAR = area at risk   ED = end-diastole/diastolic   ES = end-systole/systolic   GLP = glucagon-like peptide   I/R = ischemia and reperfusion   LCx = left circumflex coronary artery   LV = left ventricle   MI = myocardial infarction   OHdG = hydroxydeoxyguanosine   pAkt = phosphorylated Akt   PBS = phosphate-buffered saline   STEMI = ST-segment elevation myocardial infarction   TUNEL = terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling

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