Testosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src–Dependent Pathways
| Autor: | Andreia Z. Chignalia, Rhian M. Touyz, Francisco R.M. Laurindo, Augusto C. Montezano, Elke Z. Schuldt, Maria Christina W. Avellar, Lucia Rossetti Lopes, Zuleica Bruno Fortes, Maria Helena Catelli de Carvalho, Livia L Camargo, Rita C. Tostes, Glaucia E. Callera |
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| Přispěvatelé: | Universidade de São Paulo (USP), Univ Ottawa, Universidade Federal de São Paulo (UNIFESP) |
| Rok vydání: | 2012 |
| Předmět: |
Male
Vascular smooth muscle Rats Inbred WKY Muscle Smooth Vascular Flutamide chemistry.chemical_compound Cell Movement Rats Inbred SHR NADH NADPH Oxidoreductases Testosterone Cycloheximide Cells Cultured Protein Synthesis Inhibitors NADPH oxidase biology Reverse Transcriptase Polymerase Chain Reaction NOX4 NADPH Oxidase 4 NOX1 Androgens Dactinomycin NADPH Oxidase 1 cardiovascular system Signal Transduction medicine.medical_specialty hypertension Immunoblotting Proto-Oncogene Proteins pp60(c-src) c-Src FARMACOLOGIA Article Internal medicine Internal Medicine medicine Animals cardiovascular diseases NADPH Oxidases Androgen Antagonists Rats Pyrimidines Endocrinology chemistry vascular smooth muscle testosterone Apocynin biology.protein Reactive Oxygen Species |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Repositório Institucional da UNIFESP Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
| ISSN: | 1524-4563 0194-911X |
| Popis: | Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Canadian Institutes of Health Research Testosterone has been implicated in vascular remodeling associated with hypertension. Molecular mechanisms underlying this are elusive, but oxidative stress may be important. We hypothesized that testosterone stimulates generation of reactive oxygen species (ROS) and migration of vascular smooth muscle cells (VSMCs), with enhanced effects in cells from spontaneously hypertensive rats (SHRs). the mechanisms (genomic and nongenomic) whereby testosterone induces ROS generation and the role of c-Src, a regulator of redox-sensitive migration, were determined. VSMCs from male Wistar-Kyoto rats and SHRs were stimulated with testosterone (10(-7) mol/L, 0-120 minutes). Testosterone increased ROS generation, assessed by dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence (30 minutes [SHR] and 60 minutes [both strains]). Flutamide (androgen receptor antagonist) and actinomycin D (gene transcription inhibitor) diminished ROS production (60 minutes). Testosterone increased Nox1 and Nox4 mRNA levels and p47phox protein expression, determined by real-time PCR and immunoblotting, respectively. Flutamide, actinomycin D, and cycloheximide (protein synthesis inhibitor) diminished testosterone effects on p47phox. c-Src phosphorylation was observed at 30 minutes (SHR) and 120 minutes (Wistar-Kyoto rat). Testosterone-induced ROS generation was repressed by 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day]pyrimidin-4-amine (c-Src inhibitor) in SHRs and reduced by apocynin (antioxidant/NADPH oxidase inhibitor) in both strains. Testosterone stimulated VSMCs migration, assessed by the wound healing technique, with greater effects in SHRs. Flutamide, apocynin, and 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-day] pyrimidin-4-amine blocked testosterone-induced VSMCs migration in both strains. Our study demonstrates that testosterone induces VSMCs migration via NADPH oxidase-derived ROS and c-Src-dependent pathways by genomic and nongenomic mechanisms, which are differentially regulated in VSMCs from Wistar-Kyoto rats and SHRs. (Hypertension. 2012; 59: 1263-1271.). Online Data Supplement Univ São Paulo, Med Sch Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP, Brazil Univ São Paulo, Inst Biomed Sci, São Paulo, Brazil Univ São Paulo, Sch Med, Inst Heart, São Paulo, Brazil Univ Ottawa, Ottawa Hosp Res Inst, Kidney Res Ctr, Ottawa, ON, Canada Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, São Paulo, Brazil Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, São Paulo, Brazil Web of Science |
| Databáze: | OpenAIRE |
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