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 HgCl2 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 HgCl2 (first dose 4.6mgkg(-1), subsequent doses 0.07mgkg(-1)day(-1), 30days) and cultured aortic VSMC stimulated with HgCl2 (0.05-5μg/ml) were used. Treatment of rats with HgCl2 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 HgCl2: 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 HgCl2. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl2-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.
authors: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid, Spain.
authors: Andrea
authors: A
authors: Aguado
authors: María
authors: M
authors: Galán
authors: Olha
authors: O
authors: Zhenyukh
authors: Giulia A
authors: GA
authors: Wiggers
authors: Fernanda R
authors: FR
authors: Roque
authors: Santiago
authors: S
authors: Redondo
authors: Franck
authors: F
authors: Peçanha
authors: Angela
authors: A
authors: Martín
authors: Ana
authors: A
authors: Fortuño
authors: Victoria
authors: V
authors: Cachofeiro
authors: Teresa
authors: T
authors: Tejerina
authors: Mercedes
authors: M
authors: Salaices
authors: Ana M
authors: AM
authors: Briones
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000502:physiology*; D008297:Male; D008628:Mercury / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D008628:Mercury