Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Midorigaoka-higashi, Asahikawa, Japan;
Am J Physiol Heart Circ Physiol. 2013 Oct 15;305(8):H1158-67. doi: 10.1152/ajpheart.00965.2012. Epub 2013 Aug 9.
Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that processes DNA-repair function and controls cellular response to oxidative stress. Endothelial progenitor cells (EPCs) are recruited to oxidative stress-rich injured vascular walls and positively contribute to vascular repair and endothelialization. We hypothesized that APE1 functions for EPCs-mediated inhibition of neointima formation in injured vasculature. EPCs isolated from bone marrow cells of C57BL6 mice (12-16 wk old) were able to survive in the presence of hydrogen peroxide (H2O2; up to 1,000 μM) due to the highly expressed reactive oxygen species (ROS) scavengers. However, adhesion capacity of EPCs was significantly inhibited by H2O2 (100 μM) even though an intracellular ROS was retained at small level. An APE1-selective inhibitor or RNA interference-mediated knockdown of endogenous APE1 in EPCs aggravated the H2O2-mediated inhibition of EPCs-adhesion. In contrast, when APE1 was overexpressed in EPCs using an adenovirus harboring the APE1 gene (APE-EPCs), adhesion was significantly improved during oxidative stress. To examine in vivo effects of APE1 in EPCs, APE-EPCs were transplanted via the tail vein after wire-mediated injury of the mouse femoral artery. The number of adherent EPCs at injured vascular walls and the vascular repair effect of EPCs were enhanced in APE-EPCs compared with control EPCs. Among the cellular functions of EPCs, adhesion is especially sensitive to oxidative stress. APE1 enhances in vivo vascular repair effects of EPCs in part through the maintenance of adhesion properties of EPCs. APE1 may be a novel and useful target gene for effective cellular transplantation therapy.
脱嘌呤/脱嘧啶核酸内切酶 1（APE1）是一种多功能蛋白，具有处理 DNA 修复功能，并控制细胞对氧化应激的反应。内皮祖细胞（EPCs）被募集到富含氧化应激的受损血管壁，并积极促进血管修复和内皮化。我们假设 APE1 可促进 EPC 抑制受损血管中的新生内膜形成。从 12-16 周龄 C57BL6 小鼠骨髓细胞中分离的 EPCs 由于高度表达的活性氧（ROS）清除剂，能够在过氧化氢（H2O2；高达 1000 μM）存在的情况下存活。然而，即使细胞内 ROS 保持在低水平，H2O2（100 μM）也会显著抑制 EPCs 的黏附能力。EPCs 中的 APE1 选择性抑制剂或内源性 APE1 的 RNA 干扰介导的敲低会加剧 H2O2 介导的 EPCs 黏附抑制。相反，当使用携带 APE1 基因的腺病毒在 EPCs 中过表达 APE1（APE-EPCs）时，在氧化应激期间，黏附能力显著提高。为了在体内研究 APE1 在 EPCs 中的作用，在小鼠股动脉的线介导损伤后，通过尾静脉移植 APE-EPCs。与对照 EPCs 相比，在受损血管壁上黏附的 EPCs 数量和 EPCs 的血管修复效果在 APE-EPCs 中得到增强。在 EPCs 的细胞功能中，黏附对氧化应激尤其敏感。APE1 通过维持 EPCs 的黏附特性，增强了 EPCs 在体内的血管修复作用。APE1 可能是一种用于有效细胞移植治疗的新型有用的靶基因。
