Adenovirus-mediated heme oxygenase-1 gene expression stimulates apoptosis in vascular smooth muscle cells.
BACKGROUND
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into biliverdin, iron, and carbon monoxide (CO). Although HO-1 is induced in vascular smooth muscle cells (SMCs), the biological role of HO-1 in these cells has not been completely characterized.


RESULTS
In the present study, we overexpressed HO-1 in rat aortic SMCs by generating a recombinant defective adenovirus containing the rat HO-1 gene (AdHO-1) and examined the effect on SMC proliferation. Infection of SMCs with AdHO-1 resulted in a dose-dependent increase in the expression of HO-1 mRNA, protein, and activity. Infection of SMCs with AdHO-1 inhibited serum-stimulated SMC proliferation in a dose-dependent manner. In contrast, the control adenovirus expressing the green fluorescent protein failed to induce HO-1 expression and had minimal effects on SMC growth. Infection with AdHO-1 stimulated SMC apoptosis in a dose-dependent fashion, as demonstrated by DNA fragmentation, positive annexin V labeling, and caspase-3 activation. HO-1-mediated apoptosis was associated with a marked increase in the expression of the proapoptotic protein p53. Finally, the exogenous administration of biliverdin and bilirubin stimulated SMC apoptosis. In contrast, the administration of CO or iron failed to induce cell death.


CONCLUSIONS
These results demonstrate that overexpression of HO-1 or the exogenous administration of biliverdin or bilirubin stimulates SMC apoptosis. Adenovirus-mediated transfer of the HO-1 gene may provide a novel therapeutic approach in treating occlusive vascular disease.
Liu
Xiao-ming
XM
Houston VA Medical Center and the Department of Medicine, Baylor College of Medicine, Houston, Tex 77030, USA.
Chapman
Gary B
GB
Wang
Hong
H
Durante
William
W
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002248:Carbon Monoxide / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007501:Iron / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051381:Rats
D002248:Carbon Monoxide; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1