OBJECTIVE: We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS). METHODS AND RESULTS: Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS-/-) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO. Intimal thickening 21 days after cuff placement was significantly greater in mice exposed to CS compared with air (0.023+/-0.013 mm(2) versus 0.009+/-0.008 mm(2); P<0.05). iNOS inhibitor mercaptoethylguanidine-treated WT mice exposed to CS had reduced iNOS activity and intimal thickening (0.006+/-0.005 mm(2); P<0.05). Intimal thickening was significantly less in iNOS-/- mice compared with WT mice (0.006+/-0.005 mm(2); P<0.01) and was not augmented with CS (0.002+/-0.002 mm(2)). The aryl hydrocarbon receptor (AhR) was detected in arteries in vivo and in smooth muscle cells (SMCs) in vitro. CS condensate treatment of SMCs increased AhR binding to the core xenobiotic-responsive element of the iNOS promoter and increased iNOS expression. CONCLUSIONS: Increased arterial expression of iNOS, mediated at least in part by AhR signaling, may be an important mechanism by which CS increases carotid intimal thickening. CS exposure in mice was associated with increased arterial iNOS expression, superoxide production, AP-1 activation, serum NO expression, and intimal thickening. Inhibition or deletion of iNOS abrogated the effects of CS.
OBJECTIVE: We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS). METHODS AND RESULTS: Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS-/-) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO. Intimal thickening 21 days after cuff placement was significantly greater in mice exposed to CS compared with air (0.023+/-0.013 mm(2) versus 0.009+/-0.008 mm(2); P<0.05). iNOS inhibitor mercaptoethylguanidine-treated WT mice exposed to CS had reduced iNOS activity and intimal thickening (0.006+/-0.005 mm(2); P<0.05). Intimal thickening was significantly less in iNOS-/- mice compared with WT mice (0.006+/-0.005 mm(2); P<0.01) and was not augmented with CS (0.002+/-0.002 mm(2)). The aryl hydrocarbon receptor (AhR) was detected in arteries in vivo and in smooth muscle cells (SMCs) in vitro. CS condensate treatment of SMCs increased AhR binding to the core xenobiotic-responsive element of the iNOS promoter and increased iNOS expression. CONCLUSIONS: Increased arterial expression of iNOS, mediated at least in part by AhR signaling, may be an important mechanism by which CS increases carotid intimal thickening. CS exposure in mice was associated with increased arterial iNOS expression, superoxide production, AP-1 activation, serum NO expression, and intimal thickening. Inhibition or deletion of iNOS abrogated the effects of CS.
Authors: Muhammad T Salam; Hyang-Min Byun; Fred Lurmann; Carrie V Breton; Xinhui Wang; Sandrah P Eckel; Frank D Gilliland Journal: J Allergy Clin Immunol Date: 2011-11-04 Impact factor: 10.793
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