Single dose GLP-1-Tf ameliorates myocardial ischemia/reperfusion injury

Abstract

Background: Glucagon-like peptide-1 (GLP-1) has insulinomimetic, insulinotropic, and antiapoptotic properties that may make it a useful adjunct to reperfusion therapy for myocardial infarction (MI); however, GLP-1 has a short plasma half-life. Fusion of GLP-1 to human transferrin (GLP-1-Tf) significantly prolongs drug half-life.

Materials and methods: We tested the ability of single dose GLP-1-Tf to limit myocardial ischemia (30 min)/reperfusion (180 min) injury in rabbits. Nineteen animals were untreated controls. The pre-ischemic group (n=10) was given 10mg/kg of GLP-1-Tf 12 h before ischemia. Immediately after reperfusion, the post-ischemic group (n=10) received GLP-1-Tf (10 mg/kg) and the Tf group (n=4) received transferrin alone.

Results: Infarct size as a percentage of the area at risk was 59.1% ± 1.3%, 45.7% ± 1.9%, 44.1% ± 3.3%, 59.7% ± 2.0% in the control group, pre-ischemic group, post-ischemic group, and Tf group, respectively (P<0.05 for both GLP-1-Tf treatments group versus control). GLP-1-Tf reduced the apoptotic index from 4.67% ± 0.40% in the control group to 3.15% ± 0.46% in the pre-ischemic group and to 2.66% ± 0.40% in the post-ischemic group (P<0.05 for both GLP-1-Tf treatments versus control). The size of the wall motion abnormality and ejection fraction was significantly improved in the post-ischemic group relative to the control group. Serum GLP-1 levels were 239.8 ± 25.7 μg/mL in the post-ischemic group, 27.9 ± 5.8 μg/mL in the pre-ischemic group, and undetectable in the control group.

Conclusion: GLP-1-Tf limits myocardial reperfusion injury whether given prior to the onset of ischemia or given at reperfusion. GLP-1-Tf may also limit myocardial stunning at high serum levels of the drug.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Schematic of the Experimental Design

Figure 2

Representative photographs of rabbit left ventricles sectioned perpendicular to the long axis after staining with Evan’s blue dye and triphenyltetrazolium chloride. A representative heart from the pre-ischemic treatment group is depicted in (A) and a representative heart from the control group is shown in (B). These figures show the area of infarction (pale pink), risk area (red and pale pink) and non-ischemic area (purple). Note the improved myocardial salvage in the pre-ischemic treated animal compared to control.

Figure 3

The effects of GLP-1-Tf on ejection fraction as determined by serial, open-chest, quantitative, two-dimensional echocardiography. Measurements were taken at baseline (Base), at 20 minutes of ischemia (Isc-20), at the onset of reperfusion (Rep-0) and at 165 minutes of reperfusion (Rep-165) in all animals. (*p

Figure 4

The effects of GLP-1-Tf on the size of the wall motion abnormality as determined by serial, open-chest, quantitative, two-dimensional echocardiography. Measurements were taken at 20 minutes of ischemia (Isc-20), at the onset of reperfusion (Rep-0) and at 165 minutes of reperfusion (Rep-165) in all animals. (*p