MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways
Entity
UAM. Departamento de Farmacología; Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
Elsevier Inc.Date
2015-03-01Citation
10.1016/j.taap.2015.01.005
Toxicology and applied pharmacology 283.2 (2015): 127-138
ISSN
0041-008X; 1096-0333 (on line)DOI
10.1016/j.taap.2015.01.005Funded by
This work was supported by MINECO (SAF2012-36400), ISCIII 7 (RD12/0042/0024), PRONEX-CNPq/FAPES (48511935/2009). MRS was a 8 fellow of CAPES and CNPq. AMB was supported by the Ramon y Cajal 9 Program (RyC2010-06473).Project
Gobierno de España. SAF2012-36400Editor's Version
http://dx.doi.org/10.1016/j.taap.2015.01.005Subjects
Blood pressure; Cyclooxygenase-2; Lead exposure; MAPK pathway; Oxidative stress; Vascular reactivity; FarmaciaRights
© 2015 Elsevier IncAbstract
Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension
Files in this item
Google Scholar:Simões, Maylla Ronacher
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Aguado, Andrea
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Fiorim, Jonaína
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Silveira, Edna Aparecida
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Azevedo, Bruna Fernandes
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Toscano, Cindy Medice
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Zhenyukh, Olha
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Briones Alonso, Ana María
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Alonso, María Jesús
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Vassallo, Dalton Valentim
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Salaices Sánchez, Mercedes
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