Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury
Leo Timmers, José P S Henriques, Dominique P V de Kleijn, J Hans Devries, Hans Kemperman, Paul Steendijk, Cees W J Verlaan, Marjolein Kerver, Jan J Piek, Pieter A Doevendans, Gerard Pasterkamp, Imo E Hoefer, Leo Timmers, José P S Henriques, Dominique P V de Kleijn, J Hans Devries, Hans Kemperman, Paul Steendijk, Cees W J Verlaan, Marjolein Kerver, Jan J Piek, Pieter A Doevendans, Gerard Pasterkamp, Imo E Hoefer
Abstract
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.
Source: PubMed