Effect of exposure to cigarette smoke on carotid artery intimal thickening: the role of inducible NO synthase.
OBJECTIVE
We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS).


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.
Division of Cardiology and Atherosclerosis Research Center, Burns and Allen Research Institute, and the Department of Medicine, Cedars-Sinai Medical Center and David Geffen School of Medicine at University of California, Los Angeles 90048, USA.
Takeo
T
Anazawa
Paul C
PC
Dimayuga
Hongyan
H
Li
Shigemasa
S
Tani
Jason
J
Bradfield
Kuang-Yuh
KY
Chyu
Sanjay
S
Kaul
Prediman K
PK
Shah
Bojan
B
Cercek
D000818:Animals; D001273:Atmosphere Exposure Chambers; D002263:Carboxyhemoglobin / Q000032:analysis; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000235:genetics; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D016037:Single-Blind Method; D012906:Smoke / Q000009:adverse effects*; D013481:Superoxides / Q000378:metabolism; D014026:Nicotiana; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology
D006146:Guanidines; D018336:Receptors, Aryl Hydrocarbon; D012906:Smoke; D014028:Tobacco Smoke Pollution; D018808:Transcription Factor AP-1; D013481:Superoxides; D009569:Nitric Oxide; D002263:Carboxyhemoglobin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C100078:2-mercaptoethylguanidine