Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.
OBJECTIVE
Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture.


APPROACH AND RESULTS
In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs.


CONCLUSIONS
CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.
['Starke|Robert M|RM|', 'Thompson|John W|JW|', 'Ali|Muhammad S|MS|', 'Pascale|Crissey L|CL|', 'Martinez Lege|Alejandra|A|', 'Ding|Dale|D|', 'Chalouhi|Nohra|N|', 'Hasan|David M|DM|', 'Jabbour|Pascal|P|', 'Owens|Gary K|GK|', 'Toborek|Michal|M|', 'Hare|Joshua M|JM|', 'Dumont|Aaron S|AS|']
D000098:Acetophenones D017542:Aneurysm, Ruptured D000818:Animals D000975:Antioxidants D002478:Cells, Cultured D002536:Cerebral Arteries D000073865:Cigarette Smoking D004108:Dilatation, Pathologic D004195:Disease Models, Animal D002532:Intracranial Aneurysm D000090062:Kruppel-Like Factor 4 D008297:Male D018345:Mice, Knockout D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D000074624:NADPH Oxidase 1 D019255:NADPH Oxidases D018384:Oxidative Stress D010641:Phenotype D017207:Rats, Sprague-Dawley D015398:Signal Transduction D012906:Smoke D066253:Vascular Remodeling
smoke aneurysm oxygen rupture atherosclerosis subarachnoid hemorrhage