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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Downregulation of Nuclear Factor Erythroid 2-Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

Texto completo
Autor(es):
Lopes, Rheure A. [1, 2] ; Neves, Karla B. [1, 2] ; Tostes, Rita C. [1] ; Montezano, Augusto C. [2] ; Touyz, Rhian M. [2]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-05508 Sao Paulo - Brazil
[2] Univ Glasgow, Coll Med Vet & Life Sci, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark - Scotland
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Hypertension; v. 66, n. 6, p. 1240-1250, DEC 2015.
Citações Web of Science: 46
Resumo

Oxidative stress is implicated in vascular dysfunction in hypertension. Although mechanisms regulating vascular pro-oxidants are emerging, there is a paucity of information on antioxidant systems, particularly nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidants enzymes. We evaluated the vascular regulatory role of Nrf2 in hypertension and examined molecular mechanisms, whereby Nrf2 influences redox signaling in small arteries and vascular smooth muscle cells from Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Cells were stimulated with angiotensin II in the absence/presence of Nrf2 activators (bardoxolone/L-sulforaphane). Increased vascular reactive oxygen species production (chemiluminescence and amplex red) was associated with reduced Nrf2 activity in arteries (18%) and vascular smooth muscle cells (48%) in SHRSP (P<0.05 versus WKY). Expression of antioxidant enzymes, including superoxide dismutase-1 (64%), catalase (60%), peroxiredoxin 1 (75%), and glutathione peroxidase (54%), was reduced in SHRSP. L-sulforaphane reversed these effects. Angiotensin II increased nuclear accumulation of Nrf2 in vascular smooth muscle cells from WKY (197% versus vehicle), with blunted effects in SHRSP (44% versus vehicle). These responses were associated with increased antioxidant expression (superoxide dismutase-1, 32%; catalase, 42%; thioredoxin, 71%; peroxiredoxin, 1%-90%; quinone oxidoreductase, 84%; P<0.05 versus vehicle) and increased activity of superoxide dismutase-1, catalase, and thioredoxin in WKY but not in SHRSP, which exhibited increased Bach1 expression. Nrf2 activators blocked angiotensin II-induced reactive oxygen species generation. Vascular function demonstrated increased contractility (E-max WKY 113.4 +/- 5.6 versus SHRSP 159.0 +/- 8.3) and decreased endothelial-dependent relaxation (E-max WKY 88.6 +/- 3.1 versus SHRSP 74.6 +/- 3.2, P<0.05) in SHRSP, effects corrected by L-sulforaphane. Our findings suggest that Nrf2 downregulation contributes to redox-sensitive vascular dysfunction in hypertension. (AU)

Processo FAPESP: 12/12178-6 - Envolvimento da NADPH oxidase nas alterações de reatividade da artéria pudendal de camundongos diabéticos
Beneficiário:Rheure Alves Moreira Lopes
Linha de fomento: Bolsas no Brasil - Doutorado