Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: A mechanism underlying RV fibrosis associated with cigarette smoke exposure

Vang, Alexander and Clements, Richard T. and Chichger, Havovi and Kue, Nouaying and Allawzi, Ayed and O'Connell, Kelly and Jeong, Euy-Myoung and Dudley, Samuel C. Jr. and Sakhatskyy, Pavlo and Lu, Qing and Zhang, Peng and Rounds, Sharon and Choudhary, Gaurav (2017) Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: A mechanism underlying RV fibrosis associated with cigarette smoke exposure. American Journal of Physiology - Lung Cellular and Molecular Physiology, 312 (5). pp. 748-759. ISSN 1522-1504

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Official URL: http://dx.doi.org/10.1152/ajplung.00393.2016

Abstract

INTRODUCTION: Right ventricular dysfunction is associated with numerous smoking-related illnesses including chronic obstructive pulmonary disease (COPD) where it is present even in absence of pulmonary hypertension. It is unknown if exposure to cigarette smoke has direct effects on RV function and cardiac fibroblast proliferation or collagen synthesis. In this study, we evaluated cardiac function and fibrosis in mice exposed to cigarette smoke (CS) and determined mechanisms of smoke-induced changes in cardiac fibroblast signaling and fibrosis. METHODS: AKR mice were exposed to cigarette smoke for six weeks followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat cardiac fibroblasts (CF) exposed to cigarette smoke extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay. RESULTS: Mice exposed to CS had significantly decreased RV function as determined by TAPSE. There were no changes in LV parameters. RV collagen content was significantly elevated but there was no change in RV hypertrophy or pulmonary vascular muscularization. CSE directly increased cardiac fibroblast 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. CONCLUSION: CS and nicotine have direct effects on cardiac fibroblasts to induce proliferation and fibrosis which may negatively affect right heart function.

Item Type: Journal Article
Keywords: chronic obstructive pulmonary disease, fibrosis, nicotine, nicotinic acetylcholine receptor, right ventricle, COPD
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Dr Havovi Chichger
Date Deposited: 27 Mar 2017 07:52
Last Modified: 13 Feb 2019 09:27
URI: http://arro.anglia.ac.uk/id/eprint/701604

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