title: MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways.
abstract: 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/100g; subsequent doses: 0.125μg/100g, intramuscular, 30days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20μg/dL) were used. Lead blood levels of treated rats attained 21.7±2.38μg/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.
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil; Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain. Electronic address: yllars@hotmail.com.
authors.forename: Maylla Ronacher
authors.initials: MR
authors.lastname: Simões
authors.affiliation: Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aguado
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil.
authors.forename: Jonaína
authors.initials: J
authors.lastname: Fiorim
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil.
authors.forename: Edna Aparecida
authors.initials: EA
authors.lastname: Silveira
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil.
authors.forename: Bruna Fernandes
authors.initials: BF
authors.lastname: Azevedo
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil.
authors.forename: Cindy Medice
authors.initials: CM
authors.lastname: Toscano
authors.affiliation: Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
authors.forename: Olha
authors.initials: O
authors.lastname: Zhenyukh
authors.affiliation: Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Alonso
authors.affiliation: Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091, Brazil; Health Science Center of Vitória-EMESCAM, Vitória, ES CEP 29045-402, Brazil.
authors.forename: Dalton Valentim
authors.initials: DV
authors.lastname: Vassallo
authors.affiliation: Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain. Electronic address: mercedes.salaices@uam.es.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007854:Lead / Q000008:administration & dosage / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D007854:Lead; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat
keywords: Blood pressure; Cyclooxygenase-2; Lead exposure; MAPK pathway; Oxidative stress; Vascular reactivity