Abstract 13755: Glutaredoxin-1 Overexpression Enhances Akt/mk2/vegf/nfkappab-Mediated Neovascularization and Reduces Ventricular Remodeling During Chronic Myocardial Infarction
The glutathione (GSH)/Grx and GSH/thioredoxin (Trx) system regulates the cellular redox status and redox-dependent signaling pathways involving apoptosis, cell migration, proliferation and differentiation. Both Grx-1 and Trx-1 have been known to implicate in various physiological and disease-related conditions, such as immune defense, cardiac hypertrophy, myocardial infarction and hypoxia-reoxygenation. Moreover, Trx-1 was found to be novel pro-angiogenic molecule in inducing myocardial angiogenesis but the role of Grx-1 in angiogenesis during myocardial infarction (MI) still remains unclear. Hence, the present study attempted to evaluate the role and molecular mechanism of Grx1 in angiogenesis and ventricular remodeling after MI. Wild type (W) and Grx1 transgenic (Grx1Tg/+) mice were randomized into W Sham (WS), Grx1Tg/+ Sham (GS), WMI, Grx1Tg/+MI (GMI). MI was induced by permanent occlusion of LAD coronary artery. Sham groups underwent the same time matched surgical procedure without LAD ligation. Significant, reduction in infarct size (37±0.9vs.46±0.7%), apoptotic cardiomyocyte (2.8 fold) and fibrosis was observed in Grx1Tg/+ mice after MI compared to wild type MI. Further, we observed increased capillary (1.5 fold) and arteriolar density (1.3 fold) 7 days after surgical intervention with a consequent improvement in the myocardial functional parameters 30 days after MI such as decreased LVIDs (2.9±0.3vs.3.6±0.5 mm) and LVIDd (4±0.3vs.4.5±0.6 mm), and increased ejection fraction (53±3vs.42±9 %) and fractional shortening (27±1vs.20±5 %) in GMI compared to WMI. Western blot analysis showed increased expression of p-Akt, p-MK2, VEGF, Bcl-2, survivin, and DNA binding activity of NF-kappaB by gel-shift analysis in GMI when compared to WMI. Therefore in conclusion, our study identifies for the first time the potential of Grx1 overexpression in inducing angiogenesis and reduced ventricular remodeling probably via Akt/MK2/VEGF and NF-kappaB mediated pathway in the infarcted myocardium.
- © 2010 by American Heart Association, Inc.