Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease

Robert M Starke; Muhammad S Ali; Pascal M Jabbour; Stavropoula I Tjoumakaris; Fernando Gonzalez; David M Hasan; Robert H Rosenwasser; Gary K Owens; Walter J Koch; Aaron S Dumont

doi:10.1371/journal.pone.0071954

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Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease

Journal article

Open access

Peer reviewed

Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease

Robert M Starke, Muhammad S Ali, Pascal M Jabbour, Stavropoula I Tjoumakaris, Fernando Gonzalez, David M Hasan, Robert H Rosenwasser, Gary K Owens, Walter J Koch and Aaron S Dumont

PloS one, Vol.8(8), pp.e71954-e71954

2013

DOI: 10.1371/journal.pone.0071954

PMCID: PMC3743809

PMID: 23967268

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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. Methods and 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. Conclusion 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.

Phenotype

Carotid Arteries - drug effects

Carotid Arteries - metabolism

Muscle, Smooth, Vascular - metabolism

Tobacco Products - analysis

Promoter Regions, Genetic - drug effects

Carotid Arteries - cytology

Promoter Regions, Genetic - genetics

Kruppel-Like Transcription Factors - metabolism

Trans-Activators - genetics

Nuclear Proteins - genetics

Muscle, Smooth, Vascular - drug effects

Cerebrovascular Disorders - chemically induced

Smoke - adverse effects

Rats

Down-Regulation - drug effects

Muscle, Smooth, Vascular - cytology

Rats, Sprague-Dawley

Acetylation - drug effects

Muscle, Smooth, Vascular - pathology

Animals

Cell Differentiation - drug effects

Genetic Markers - genetics

Carotid Arteries - pathology

Cerebrovascular Disorders - genetics

Histone Deacetylase 2 - metabolism

Histones - metabolism

Cerebrovascular Disorders - pathology

DNA Methylation - drug effects

Kruppel-Like Transcription Factors - antagonists & inhibitors

Details

Title: Subtitle: Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease
Creators: Robert M Starke - 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
Muhammad S Ali
Pascal M Jabbour
Stavropoula I Tjoumakaris
Fernando Gonzalez
David M Hasan
Robert H Rosenwasser
Gary K Owens
Walter J Koch
Aaron S Dumont
Resource Type: Journal article
Publication Details: PloS one, Vol.8(8), pp.e71954-e71954
DOI: 10.1371/journal.pone.0071954
PMID: 23967268
PMCID: PMC3743809
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: T32 HL007544 / NHLBI NIH HHS R01 HL57353 / NHLBI NIH HHS R01 HL098538 / NHLBI NIH HHS R01 HL121008 / NHLBI NIH HHS T32 HL007284 / NHLBI NIH HHS P01 HL091799 / NHLBI NIH HHS R01 HL087867 / NHLBI NIH HHS R01 HL057353 / NHLBI NIH HHS P01 HL07544 / NHLBI NIH HHS K08 NS067072 / NINDS NIH HHS
Language: English
Date published: 2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurosurgery; Otolaryngology
Record Identifier: 9984040229202771

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