Antiapoptotic action of carbon monoxide on cultured vascular smooth muscle cells.
Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) from the degradation of heme by the enzyme heme oxygenase. Because recent studies indicate that CO influences the properties of vascular SMCs, we examined whether this diatomic gas regulates apoptosis in vascular SMCs. Treatment of cultured rat aortic SMCs with a cytokine cocktail consisting of interleukin-1beta (5 ng/ml), tumor necrosis factor-alpha (20 ng/ml), and interferon-gamma (200 U/ml) for 48 hr stimulated apoptosis, as demonstrated by DNA laddering, caspase-3 activation, and annexin V staining. However, the exogenous addition of CO (200 ppm) completely blocked cytokine-mediated apoptosis. The antiapoptotic action of CO was partially reversed by the soluble guanylate cyclase inhibitor, H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM). In contrast, the p38 mitogen-activated protein kinase inhibitor, SB203580 (10 microM), had no effect on SMC apoptosis. These findings indicate that CO is a potent inhibitor of vascular SMC apoptosis and that it blocks apoptosis, in part, by activating the cGMP signaling pathway. The ability of CO to inhibit vascular SMC apoptosis may play a critical role in attenuating lesion formation at sites of arterial damage.
Liu
Xiao-Ming
XM
Houston VA Medical Center and the Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Chapman
Gary B
GB
Peyton
Kelly J
KJ
Schafer
Andrew I
AI
Durante
William
W
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010069:Oxadiazoles / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism; D051381:Rats
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010069:Oxadiazoles; D011725:Pyridines; D011810:Quinoxalines; D002248:Carbon Monoxide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580