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Title: Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

Abstract

Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercurymore » in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces MAPK activation, oxidative stress and COX-2 expression. ► Inhibition of MAPK reduces HgCl{sub 2}-induced oxidative stress and COX-2 expression. ► Inhibition of MAPK, oxidative stress and COX-2 restores the altered cell proliferation and size.« less

Authors:
; ; ; ;  [1];  [2];  [1];  [3];  [4];  [5];  [2];  [1];
  1. Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain)
  2. Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain)
  3. Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, 28922, Alcorcón (Spain)
  4. Área de Ciencias Cardiovasculares, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008, Pamplona (Spain)
  5. Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain)
Publication Date:
OSTI Identifier:
22285272
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 268; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; AORTA; CELL PROLIFERATION; CHRONIC EXPOSURE; GENES; INFLAMMATION; MERCURY; MERCURY CHLORIDES; OXIDASES; OXIDATION; OXYGEN; RATS; STRESSES; SUPEROXIDE DISMUTASE

Citation Formats

Aguado, Andrea, Galán, María, Zhenyukh, Olha, Wiggers, Giulia A., Roque, Fernanda R., Redondo, Santiago, Peçanha, Franck, Martín, Angela, Fortuño, Ana, Cachofeiro, Victoria, Tejerina, Teresa, Salaices, Mercedes, E-mail: mercedes.salaices@uam.es, and and others. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.01.030.
Aguado, Andrea, Galán, María, Zhenyukh, Olha, Wiggers, Giulia A., Roque, Fernanda R., Redondo, Santiago, Peçanha, Franck, Martín, Angela, Fortuño, Ana, Cachofeiro, Victoria, Tejerina, Teresa, Salaices, Mercedes, E-mail: mercedes.salaices@uam.es, & and others. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways. United States. doi:10.1016/J.TAAP.2013.01.030.
Aguado, Andrea, Galán, María, Zhenyukh, Olha, Wiggers, Giulia A., Roque, Fernanda R., Redondo, Santiago, Peçanha, Franck, Martín, Angela, Fortuño, Ana, Cachofeiro, Victoria, Tejerina, Teresa, Salaices, Mercedes, E-mail: mercedes.salaices@uam.es, and and others. Mon . "Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways". United States. doi:10.1016/J.TAAP.2013.01.030.
@article{osti_22285272,
title = {Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways},
author = {Aguado, Andrea and Galán, María and Zhenyukh, Olha and Wiggers, Giulia A. and Roque, Fernanda R. and Redondo, Santiago and Peçanha, Franck and Martín, Angela and Fortuño, Ana and Cachofeiro, Victoria and Tejerina, Teresa and Salaices, Mercedes, E-mail: mercedes.salaices@uam.es and and others},
abstractNote = {Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces MAPK activation, oxidative stress and COX-2 expression. ► Inhibition of MAPK reduces HgCl{sub 2}-induced oxidative stress and COX-2 expression. ► Inhibition of MAPK, oxidative stress and COX-2 restores the altered cell proliferation and size.},
doi = {10.1016/J.TAAP.2013.01.030},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 268,
place = {United States},
year = {Mon Apr 15 00:00:00 EDT 2013},
month = {Mon Apr 15 00:00:00 EDT 2013}
}