Abstract 13787: Ischemic Postconditioning Triggers Beta-Catenin-Mediated VEGF-Dependent Increased Angiogenesis and Reduced Ventricular Remodeling in Mouse Ischemic Reperfused Myocardium
Ischemic postconditioning (IPoC) has generated interest as a mechanical intervention against myocardial ischemia/reperfusion (I/R) injury, but its effect on angiogenesis remains elusive. Present study attempts to address whether beta-catenin mediated VEGF activation plays role in IPoC-mediated angiogenesis. Male CD1 mice were divided into 5 groups, Control Sham (CS), I/R, IPoC, Ad-sh-beta(b)-cat+IPoC and Ad-sh-scramble+IPoC. Mice were subjected to 30 min of regional ischemia followed by various duration of reperfusion depending on the parameters studied. For IPoC, 3 cycles of 10s reperfusion and 10s re-occlusion was applied at the onset of reperfusion. To observe the effect of beta-catenin inhibition, Ad-sh-b-cat or Ad-sh-scr (1X109 PFU) was administered intramyocardially at four different sites 48h prior to IPoC. We observed, reduction in infarct size (28±1vs.36±0.9%), apoptotic cardiomyocytes (20±2vs.130±28 counts/100HPF) and myocardial fibrosis, and increase in capillary (2970±210vs.2258±162 counts/mm2) and arteriolar (60±2vs.37±6 counts/mm2) density with a consequent improvement in myocardial functions such as increased ejection fraction (65±4vs.52±1%), fractional shortening (35±3vs.26±1%) as assessed by echocardiography in the IPoC group compared to non-IPoC. Immunoblot analysis revealed, increased p-GSK-3b (1.4 fold), b-catenin nuclear translocation (1.5 fold), VEGF (1.3 fold), Ang-1 (1.5 fold), Bcl-2 (1.6 fold), survivin (1.4 fold) levels in IPoC compared to non-IPoC. On the other hand, Ad-sh-b-cat administration prior to IPoC almost abolished the expression of b-cat, VEGF, Ang-1, Bcl-2 and survivin. In addition, IPoC mediated cardioprotective effect was significantly blocked by the addition of Ad-sh-b-cat 48h prior to IPoC which was demonstrated increased infarct size and fibrosis indicating the possible role of b-catenin in triggering VEGF and increased angiogenesis and cardioprotection by IPoC. In conclusion, the present study identifies for the first time the potential effect of IPoC, at the onset of reperfusion, induces angiogenesis via GSK-3b, b-catenin, VEGF, Ang-1, which leads to reduced cell death via Bcl-2 and survivin followed by decreased ventricular remodeling.
- © 2010 by American Heart Association, Inc.