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


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.


CONCLUSIONS
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.
Matsubara
Muneaki
M
Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19036, USA.
Kanemoto
Shinya
S
Leshnower
Bradley G
BG
Albone
Earl F
EF
Hinmon
Robin
R
Plappert
Theodore
T
Gorman
Joseph H
JH
Gorman
Robert C
RC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004452:Echocardiography; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014168:Transferrin / Q000627:therapeutic use*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D052216:Glucagon-Like Peptide 1