Apurinic/apyrimidinic endonucelase 1 maintains adhesion of endothelial progenitor cells and reduces neointima formation.
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.
Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Midorigaoka-higashi, Asahikawa, Japan;
Atsushi
A
Yamauchi
Jun-ichi
J
Kawabe
Maki
M
Kabara
Motoki
M
Matsuki
Akira
A
Asanome
Tatsuya
T
Aonuma
Hisanobu
H
Ohta
Naofumi
N
Takehara
Taku
T
Kitagawa
Naoyuki
N
Hasebe
D000818:Animals; D001808:Blood Vessels / Q000293:injuries; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology* / Q000637:transplantation; D016166:Free Radical Scavengers; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058426:Neointima / Q000503:physiopathology*; D016877:Oxidants / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013234:Stem Cells / Q000502:physiology*
D016166:Free Radical Scavengers; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C085108:APEX1 protein, human; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
apurinic/apyriμidinic endonuclease 1; endothelial progenitor cells; oxidative stress; vascular remodeling