Abstract 14862: Enhanced inhibition of Neointimal Hyperplasia by Overexpression of Apurinic/apyrimidinic Endonuclease (APE1) in Endothelial Progenitor Cells
Introduction: Bone marrow derived endothelial progenitor cells (EPCs) are recruited at injured vascular walls and positively contribute to endothelialization, vascular repair. However, its effects are limited by cardiovascular risk factors such as aging. APE1 is a multifunctional proteins possessing both DNA-repair and controlling cellular response to oxidative stress. We hypothesized that the expression of anti-oxidative DNA-repairing protein, APE1 in EPCs could function against unfavorable situation of inflammation-induced oxidative stress in vascular remodeling process.
Methods and Results: C57BL6 male mice, of which bone marrow (BM) were transplanted with BM cells isolated from young (12-week old) or aged (1.5-year old) mice (BMT-young or BMT-aged) were prepared and applied to operation of wire-mediated vascular injury. Wire-injury induced neointimal thickness in BMT-aged was increased compared to that of BMT-young. This enhanced remodeling was cancelled by infusion of EPCs isolated from young mice. The expression level of APE1 gene was enhanced in response to treatment with pro-inflammatory cytokine, tumor necrotic factor (TNF-a) in young EPCs, but not aged EPCs to protect from cytokine-induced apoptosis. Next, EPCs were transduced with adenovirus vectors expressing human APE1, or green fluorescent protein (APE-EPCs or GFP-EPCs). Wire-injury induced neointimal thickening was decreased by infusion of GFP-EPCs relative to the saline-infusion control. Neointimal thickness was further reduced in vessels treated with APE-EPCs compared to that of GFP-EPCs(Fig) .
Conclusion: APE1 in EPCs is important to function aganist oxidative stress and exhibit their in vivo vascular repairing effects. Transplantation of APE1-overexpressing EPCs may serve as a novel and useful therapeutic strategy.
- © 2010 by American Heart Association, Inc.