Reciprocal regulation of angiopoietin-1 and angiopoietin-2 following myocardial infarction in the rat.
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.
Sandhu
Reena
R
Terrence Donnelly Heart Center, St. Michael's Hospital, Toronto, Ontario, Canada.
Teichert-Kuliszewska
Krystyna
K
Nag
Sukriti
S
Proteau
Gerald
G
Robb
Malcolm J
MJ
Campbell
Andrew I M
AI
Kuliszewski
Michael A
MA
Kutryk
Michael J B
MJ
Stewart
Duncan J
DJ
D042683:Angiopoietin-1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D042702:Angiopoietin-2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042787:Receptor, TIE-2