TY - JOUR
T1 - Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts:A mechanism underlying RV fibrosis associated with cigarette smoke exposure
AU - Vang, Alexander
AU - Clements, Richard T.
AU - Chichger, Havovi
AU - Kue, Nouaying
AU - Allawzi, Ayed
AU - O’Connell, Kelly
AU - Jeong, Euy Myoung
AU - Dudley, Samuel C.
AU - Sakhatskyy, Pavlo
AU - Lu, Qing
AU - Zhang, Peng
AU - Rounds, Sharon
AU - Choudhary, Gaurav
N1 - Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/5/4
Y1 - 2017/5/4
N2 - Right ventricular (RV) dysfunction is associated with numerous smokingrelated 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.
AB - Right ventricular (RV) dysfunction is associated with numerous smokingrelated 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.
KW - Chronic obstructive pulmonary disease
KW - Fibrosis
KW - Nicotine
KW - Nicotinic acetylcholine receptor
KW - Right ventricle
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U2 - 10.1152/ajplung.00393.2016
DO - 10.1152/ajplung.00393.2016
M3 - Article
C2 - 28258105
AN - SCOPUS:85018454238
SN - 1040-0605
VL - 312
SP - L669-L677
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 5
ER -