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

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

doi:10.1161/ATVBAHA.117.310478

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

Journal article

Open access

Peer reviewed

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

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, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.38(3), pp.610-621

03/2018

DOI: 10.1161/ATVBAHA.117.310478

PMCID: PMC5823774

PMID: 29348119

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https://doi.org/10.1161/ATVBAHA.117.310478View

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Abstract

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. 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. 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.

Vascular Remodeling

Oxidative Stress

Myocytes, Smooth Muscle - pathology

NADPH Oxidases - metabolism

Aneurysm, Ruptured - prevention & control

Male

Intracranial Aneurysm - prevention & control

Smoke

Acetophenones - pharmacology

NADPH Oxidases - genetics

Intracranial Aneurysm - enzymology

Dilatation, Pathologic

Disease Models, Animal

Cigarette Smoking - adverse effects

Signal Transduction

Intracranial Aneurysm - genetics

Myocytes, Smooth Muscle - enzymology

NADPH Oxidases - antagonists & inhibitors

Cells, Cultured

NADPH Oxidase 1 - genetics

Antioxidants - pharmacology

Rats, Sprague-Dawley

Mice, Knockout

Muscle, Smooth, Vascular - pathology

Phenotype

Aneurysm, Ruptured - enzymology

Animals

Cerebral Arteries - enzymology

Cerebral Arteries - pathology

NADPH Oxidase 1 - metabolism

Aneurysm, Ruptured - pathology

Intracranial Aneurysm - pathology

Aneurysm, Ruptured - genetics

Muscle, Smooth, Vascular - enzymology

Details

Title: Subtitle: Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis
Creators: Robert M Starke - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.). RStarke@med.miami.edu
John W Thompson - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Muhammad S Ali - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Crissey L Pascale - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Alejandra Martinez Lege - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Dale Ding - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Nohra Chalouhi - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
David M Hasan - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Pascal Jabbour - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Gary K Owens - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Michal Toborek - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Joshua M Hare - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Aaron S Dumont - From the Department of Neurological Surgery & Radiology, University of Miami Cerebrovascular Initiative (R.M.S., J.W.T.), Department of Biochemistry and Molecular Biology (M.T.), and Department of Cardiology and Molecular and Cellular Pharmacology (J.M.H.), University of Miami, FL; Department of Neurosurgery, University of Iowa, Iowa City (M.S.A., D.M.H.); Department of Neurological Surgery, Tulane University, New Orleans, LA (C.L.P., A.M.L., A.S.D.); Department of Neurosurgery (D.D.) and Department of Molecular Physiology & Biophysics, Robert M. Berne Cardiovascular Research Center (G.K.O.), University of Virginia, Charlottesville; and Department of Neurosurgery, Thomas Jefferson University, Philadelphia, PA (N.C., P.J.)
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.38(3), pp.610-621
Publisher: United States
DOI: 10.1161/ATVBAHA.117.310478
PMID: 29348119
PMCID: PMC5823774
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: R01 HL110737 / NHLBI NIH HHS R01 HL098538 / NHLBI NIH HHS UM1 HL113460 / NHLBI NIH HHS R03 NS079227 / NINDS NIH HHS K08 NS082363 / NINDS NIH HHS R01 HL107110 / NHLBI NIH HHS R01 HL084275 / NHLBI NIH HHS R01 HL094849 / NHLBI NIH HHS R01 HL087867 / NHLBI NIH HHS R01 HL057353 / NHLBI NIH HHS K08 NS067072 / NINDS NIH HHS
Language: English
Date published: 03/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurosurgery; Otolaryngology
Record Identifier: 9984040338002771

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