Journal Article

Cigarette Smoke Modulates Vascular Smooth Muscle Phenotype: Implications for Carotid and Cerebrovascular Disease

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

2013

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetylation / Acetylation - drug effects / Actin / Animals / Arteries / Arteriosclerosis / Atherosclerosis / Biology / Carotid arteries / Carotid Arteries - cytology / Carotid Arteries - drug effects / Carotid Arteries - metabolism / Carotid Arteries - pathology / Carotid artery / Cell culture / Cell Differentiation - drug effects / Cerebral blood flow / Cerebrovascular Disorders - chemically induced / Cerebrovascular Disorders - genetics / Cerebrovascular Disorders - pathology / Chromatin / Cigarette smoke / Cigarettes / Circulatory system / Cytokines / DNA methylation / DNA Methylation - drug effects / Down-Regulation - drug effects / Epigenetic inheritance / Epigenetics / Exposure / Gene expression / Genes / Genetic aspects / Genetic Markers - genetics / Genomics / Histone Deacetylase 2 - metabolism / Histones - metabolism / IL-1β / Inflammation / Kinases / KLF4 protein / Kruppel-Like Factor 4 / Kruppel-Like Transcription Factors - antagonists & inhibitors / Kruppel-Like Transcription Factors - metabolism / Laboratory animals / Major histocompatibility complex / Medicine / Methylation / Modulation / Monocyte chemoattractant protein 1 / Muscle contraction / Muscle proteins / Muscle, Smooth, Vascular - cytology / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - pathology / Muscles / NF-κB protein / Nicotine / Nuclear Proteins - genetics / Pathogenesis / Phenotype / Precipitation (Meteorology) / Promoter Regions, Genetic - drug effects / Promoter Regions, Genetic - genetics / Rats / Rats, Sprague-Dawley / Risk factors / RNA / Rodents / Smoke / Smoke - adverse effects / Smoking / Smooth muscle / Studies / Tobacco Products - analysis / Trans-Activators - genetics / Transcription activation / Transcription factors / Tumor necrosis factor-α / Vascular surgery