title: Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure.
abstract: Right ventricular (RV) dysfunction is associated with numerous smoking-related illnesses, including chronic obstructive pulmonary disease (COPD), in which it is present even in the absence of pulmonary hypertension. It is unknown whether exposure to cigarette smoke (CS) has direct effects on RV function and cardiac fibroblast (CF) proliferation or collagen synthesis. In this study, we evaluated cardiac function and fibrosis in mice exposed to CS and determined mechanisms of smoke-induced changes in CF signaling and fibrosis. AKR mice were exposed to CS for 6 wk followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat CFs exposed to CS extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay. Mice exposed to CS had significantly decreased RV function, as determined by tricuspid annular plane systolic excursion. There were no changes in left ventricular parameters. RV collagen content was significantly elevated, but there was no change in RV hypertrophy or pulmonary vascular muscularization. CSE directly increased CF proliferation and collagen content in CF. Nicotine alone reproduced these effects. CSE and nicotine-induced fibroblast proliferation and collagen content were mediated through α7 nicotinic acetylcholine receptors and were dependent on PKC-α, PKC-δ, and reduced p38-MAPK phosphorylation. CS and nicotine have direct effects on CFs to induce proliferation and fibrosis, which may negatively affect right heart function.
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vang
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Surgery, Rhode Island Hospital, Providence, Rhode Island; and.|Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Havovi
authors.initials: H
authors.lastname: Chichger
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.
authors.forename: Nouaying
authors.initials: N
authors.lastname: Kue
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island.
authors.forename: Ayed
authors.initials: A
authors.lastname: Allawzi
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Kelly
authors.initials: K
authors.lastname: O'Connell
authors.affiliation: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.|Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.affiliation: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.|Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Pavlo
authors.initials: P
authors.lastname: Sakhatskyy
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Qing
authors.identifier: 0000-0002-4088-6200
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.|Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Sharon
authors.initials: S
authors.lastname: Rounds
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; gaurav_choudhary@brown.edu.|Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Gaurav
authors.identifier: 0000-0001-9343-5481
authors.initials: G
authors.lastname: Choudhary
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008806:Mice, Inbred AKR; D009206:Myocardium / Q000473:pathology*; D009538:Nicotine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000009:adverse effects*; D066253:Vascular Remodeling / Q000187:drug effects; D018497:Ventricular Dysfunction, Right / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases
keywords: chronic obstructive pulmonary disease; fibrosis; nicotine; nicotinic acetylcholine receptor; right ventricle