Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

Authors

Robert M. Starke, University of Miami
John W. Thompson, University of Miami
Muhammad S. Ali, University of Iowa
Crissey L. Pascale, Tulane University
Alejandra Martinez Lege, Tulane University
Dale Ding, University of Virginia
Nohra Chalouhi, Thomas Jefferson UniversityFollow
David M. Hasan, University of Iowa
Pascal Jabbour, Thomas Jefferson UniversityFollow
Gary K Owens, University of Virginia
Michal Toborek, University of Miami
Joshua M. Hare, University of Miami
Aaron S. Dumont, Tulane University

Document Type

Article

Publication Date

3-1-2018

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 38, Issue 3, March 2018, Pages 610-621.

The published version is available at https://doi.org/10.1161/ATVBAHA.117.310478. Copyright © American Heart Association, Inc.

Abstract

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.

Recommended Citation

Starke, Robert M.; Thompson, John W.; Ali, Muhammad S.; Pascale, Crissey L.; Martinez Lege, Alejandra; Ding, Dale; Chalouhi, Nohra; Hasan, David M.; Jabbour, Pascal; Owens, Gary K; Toborek, Michal; Hare, Joshua M.; and Dumont, Aaron S., "Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis." (2018). Department of Neurosurgery Faculty Papers. Paper 107.
https://jdc.jefferson.edu/neurosurgeryfp/107

PubMed ID

29348119

Language

English