Carbon monoxide inhibits apoptosis in vascular smooth muscle cells.
OBJECTIVE
Carbon monoxide (CO) is generated from vascular smooth muscle cells via the degradation of heme by the enzyme heme oxygenase-1. Since smooth muscle cell apoptosis is associated with numerous vascular disorders, we investigated whether CO regulates apoptosis in vascular smooth muscle.


RESULTS
Treatment of cultured rat aortic smooth muscle cells with a combination of cytokines (interleukin-1beta, 5 ng/ml; tumor necrosis factor-alpha, 20 ng/ml; interferon-gamma, 200 U/ml) for 48 h stimulated apoptosis, as demonstrated by DNA laddering, annexin V binding, and caspase-3 activation. However, the exogenous administration of CO inhibited cytokine-mediated apoptosis. The antiapoptotic action of CO was partially dependent on the activation of soluble guanylate cyclase and was associated with the inhibition of mitochondrial cytochrome c release and with the suppression of p53 expression. Incubation of smooth muscle cells with the cytokines also resulted in a pronounced increase in heme oxygenase-1 protein after 24 h of stimulation. The addition of the heme oxygenase inhibitor, zinc protoporphyrin-IX, or the CO scavenger, hemoglobin, stimulated apoptosis following 24 h of cytokine exposure.


CONCLUSIONS
These results demonstrate that CO, either administered exogenously or endogenously derived from heme oxygenase-1 activity, inhibits vascular smooth muscle cell apoptosis. The ability of CO to block smooth muscle cell apoptosis may play an important role in blocking lesion formation at sites of vascular injury.
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Xiao-ming
XM
Liu
Gary B
GB
Chapman
Kelly J
KJ
Peyton
Andrew I
AI
Schafer
William
W
Durante
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology* / Q000502:physiology; D018929:Cell Culture Techniques; D003574:Cytochrome c Group / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D003574:Cytochrome c Group; D016207:Cytokines; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase