title: Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease.
abstract: BACKGROUND
  The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established.
  
  
  RESULTS
  In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation.
  
  
  CONCLUSIONS
  CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke.
authors: Joseph and Marie Field Cerebrovascular Research Laboratory, Division of Neurovascular and Endovascular Surgery, Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Robert M
authors: RM
authors: Starke
authors: Muhammad S
authors: MS
authors: Ali
authors: Pascal M
authors: PM
authors: Jabbour
authors: Stavropoula I
authors: SI
authors: Tjoumakaris
authors: Fernando
authors: F
authors: Gonzalez
authors: David M
authors: DM
authors: Hasan
authors: Robert H
authors: RH
authors: Rosenwasser
authors: Gary K
authors: GK
authors: Owens
authors: Walter J
authors: WJ
authors: Koch
authors: Aaron S
authors: AS
authors: Dumont
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002339:Carotid Arteries / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005819:Genetic Markers / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products / Q000032:analysis*; D015534:Trans-Activators / Q000235:genetics; D000099251:Myocardin
chemical_list: D005819:Genetic Markers; D056464:Histone Deacetylase 2; D006657:Histones; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012906:Smoke; D015534:Trans-Activators; D000099251:Myocardin; C000715469:Klf4 protein, rat
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