After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells.
BACKGROUND
Heme oxygenase-1 (HO-1), a heme degradation enzyme with multiple vasoprotective functions, is systemically induced in pathophysiological states associated with oxidative stress.


OBJECTIVE
To evaluate the impact of systemic HO-1 expression on circulating endothelial progenitor cells (EPCs) and re-endothelialization after vascular injury in an animal model.


METHODS
Mice received an intravenous (i.v.) injection of the adenovirus-bearing HO-1 gene (Adv-HO-1). The serum levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were determined by ELISA and gene expression examined by quantitative real-time PCR. Circulating EPCs were characterized by flow cytometry and in vitro culture. EPC recruitment and re-endothelialization in injured arteries were assessed in mice receiving GFP+-bone marrow transplantation and guide wire-induced carotid injury. The effect of carbon monoxide (CO), a byproduct from heme degradation by HO-1, was assessed by exposing mice to 250 p.p.m. CO for 2 h day(-1).


RESULTS
Systemic HO-1 induction led to elevated serum levels of VEGF and SDF-1 and an increase in circulating EPCs. The re-endothelialization of denuded vessels was accelerated in mice with systemic HO-1 overexpression. A further experiment demonstrated that both EPC mobilization and re-endothelialization were significantly attenuated in mice with HO-1 deficiency. The increase in EPC mobilization and enhanced re-endothelialization was also observed in mice exposed to CO prior to carotid injury. The CO-mediated effect was associated with an increase in circulating SDF-1 but not VEGF.


CONCLUSIONS
These findings support a vital role of HO-1 and its reaction byproduct, CO, in vascular repair through enhancing EPC mobilization.
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
H-H
HH
Lin
Y-H
YH
Chen
S-F
SF
Yet
L-Y
LY
Chau
D000818:Animals; D001808:Blood Vessels / Q000293:injuries*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000097:blood / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics
D054377:Chemokine CXCL12; D042461:Vascular Endothelial Growth Factor A; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1