Downregulation of Nuclear Factor Erythroid 2-Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension.
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 (Emax WKY 113.4±5.6 versus SHRSP 159.0±8.3) and decreased endothelial-dependent relaxation (Emax 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.
From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (R.A.L., K.B.N., A.C.M., R.M.T.); and Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (R.A.L., K.B.N., R.C.T.).
Rhéure A
RA
Lopes
From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (R.A.L., K.B.N., A.C.M., R.M.T.); and Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (R.A.L., K.B.N., R.C.T.).
Karla B
KB
Neves
From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (R.A.L., K.B.N., A.C.M., R.M.T.); and Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (R.A.L., K.B.N., R.C.T.).
Rita C
RC
Tostes
From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (R.A.L., K.B.N., A.C.M., R.M.T.); and Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (R.A.L., K.B.N., R.C.T.).
Augusto C
AC
Montezano
From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (R.A.L., K.B.N., A.C.M., R.M.T.); and Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (R.A.L., K.B.N., R.C.T.). rhian.touyz@glasgow.ac.uk.
Rhian M
RM
Touyz
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D011189:Potassium Chloride; D002374:Catalase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000109:Acetylcholine
Bach 1; NF-E2-related factor 2; hypertension; reactive oxygen species; vascular resistance