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

Authors

• Robert M Starke
• John W Thompson
• Muhammad S Ali
• Crissey L Pascale
• Alejandra Martinez Lege
• Dale Ding
• Nohra Chalouhi
• David M Hasan
• Pascal Jabbour
• Gary K Owens
• Michal Toborek
• Joshua M Hare
• Aaron S Dumont

Publication/Presentation Date

3-1-2018

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

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.

Volume

38

Issue

3

First Page

610

Last Page

621

ISSN

1524-4636

Published In/Presented At

Starke, R. M., Thompson, J. W., Ali, M. S., Pascale, C. L., Martinez Lege, A., Ding, D., Chalouhi, N., Hasan, D. M., Jabbour, P., Owens, G. K., Toborek, M., Hare, J. M., & Dumont, A. S. (2018). Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis. Arteriosclerosis, thrombosis, and vascular biology, 38(3), 610–621. https://doi.org/10.1161/ATVBAHA.117.310478

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

29348119

Department(s)

Administration and Leadership

Document Type

Article