NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes
NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes
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DOI：
10.2353/ajpath.2006.060042
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发表时间：
2006-08-01
影响因子：
6
通讯作者：
Silvestre, Jean-Sebastien
中科院分区：
文献类型：
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作者：
Ebrahimian, Teni G.;Heymes, Christophe;Silvestre, Jean-Sebastien
我们假设糖尿病诱导的氧化应激可能影响缺血后新生血管形成。在野生型或gp 91（phox）缺陷型对照或I型糖尿病小鼠或用抗氧化剂N-乙酰-L-半胱氨酸（NAC）或用体内电转移编码显性阴性Rac 1的质粒（50 μ g）处理21天的动物中研究单侧股动脉结扎的反应。糖尿病小鼠缺血后新生血管减少与下调血管内皮生长因子-A蛋白水平有关。在糖尿病动物血管内皮生长因子水平和缺血后新血管形成恢复到非糖尿病水平的清除活性氧（ROS）的NAC管理或抑制活性氧产生的gp 91（phox）缺陷或管理显性负Rac 1。最后，糖尿病降低了贴壁骨髓来源的单核细胞（BM-MNCs）分化为内皮祖细胞的能力。NAC（3 mmol/L）、夹竹桃黄素（200 μ mol/L）或P38 MAPK抑制剂LY 333351（10 μ mol/L）处理可使糖尿病BM-MNCs衍生的内皮祖细胞集落数量分别增加1.5、1.6和1.5倍（P < 0.05）。在缺血性后肢模型中，注射从NAG处理的或gp 91（Phox）缺陷的糖尿病小鼠分离的糖尿病BM-MNCs使新血管形成增加了类似于未处理的糖尿病BM-MNCs的1.5倍（P < 0.05）。因此，抑制NADPH氧化酶衍生的ROS过度产生改善了血管生成和血管生成过程，并恢复缺血后新生血管形成在I型糖尿病小鼠。
We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type I diabetic mice or in animals treated with the anti-oxidant N-acetyl-L-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 mu g) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 mu mol/L), or the P38MAPK inhibitor LY333351 (10 mu mol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAG treated or gp91(Phox)-deficient diabetic mice increased neovascularization by similar to 1.5-fold greater than un-treated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type I diabetic mice.