© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Reciprocal regulation of angiopoietin-1 and angiopoietin-2 following myocardial infarction in the rat*
aTerrence Donnelly Heart Center, St. Michael's Hospital, Toronto, Ontario, Canada
bThe Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
cThe Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
dThe Department of Medicine, University of Toronto, Toronto, Ontario, Canada
* Corresponding author. Division of Cardiology, Terrence Donnelly Heart Center, St. Michael's Hospital, 30 Bond Street, Room 7081, Queen Wing, Toronto, Ontario, Canada M5B 1W8. Tel.: +1-416-864-5724; fax: +1-416-864-5914. E-mail address: stewartd{at}smh.toronto.on.ca
Objective: This study sought to characterize changes in the angiopoietin system in a rat model of myocardial infarction (MI). Background: Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) bind to the endothelial-specific receptor tyrosine kinase, TIE-2. Ang-2 has been suggested to be an antagonist of TIE-2, possibly acting to release endothelial cells from the tonic stabilizing influence of Ang-1. However, on prolonged exposure, Ang-2 has been shown to acquire agonistic activity at TIE-2, raising the possibility that this isoform may play a direct role in neovascularization. Methods: Sprague–Dawley rats were subjected to left coronary ligation and myocardial tissues were harvested from the infarct and peri-infarct regions, or from non-infarcted myocardium. Changes in gene expression were determined by RT-PCR and confirmed by Northern analysis. Changes in protein expression were confirmed by Western analysis and immunocytochemistry, and TIE-2 activity was determined by immunoprecipitation with anti-TIE-2 and antiphosphotyrosine immunoblotting. Results: At 24 h, Ang-1 mRNA and protein expression within the infarct and peri-infarct regions were decreased compared to non-infarcted myocardium, whereas Ang-2 mRNA levels were markedly increased and TIE-2 expression was unchanged. Immunohistochemical staining revealed Ang-1 and TIE-2 immunoreactivity localized to vascular endothelium. In the infarct territory, Ang-2 immunostaining was localized primarily to invading leukocytes at 24 h. At 1 week, Ang-1 expression was partially restored, whereas Ang-2 expression remained elevated. At the time of peak elevation in Ang-2, Tie2 phosphorylation was found to be markedly increased, consistent with receptor activation. Conclusions: Thus, myocardial ischemia induced by left coronary artery ligation resulted in a sustained increase in Ang-2 expression and a reciprocal decrease in Ang-1, consistent with a predominant role for Ang-2 in the angiogenic response to MI.
KEYWORDS Angiogenesis; Infarction; Ischemia; Growth factors; Endothelial receptors
1 RS and KT-K contributed equally to this study.
* This work was supported by grants from the Canadian Institutes of Health Research (Award #62695) and the Heart and Stroke Foundation of Ontario (Award #NA-4789).
Time for primary review 27 days
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