Abstract
Oxidative stress is well known to lead to vascular dysfunction. Thioredoxin reductase (TrxR) catalyzes the reduction of oxidized thioredoxin. Reduced thioredoxin plays a role in cellular antioxidative defense and in decreasing S-nitrosylation. It is not known whether TrxR affects vascular reactivity. We hypothesized that TrxR inhibition decreases vascular relaxation via increased oxidative stress and S-nitrosylation. Aortic rings from C57BL/6 mice were treated with the TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB), or auranofin for 30 minutes. Vascular relaxation to acetylcholine was measured in the rings contracted with phenylephrine. DNCB and auranofin reduced relaxation compared with vehicle (vehicle Emax = 71 ± 3%, DNCB Emax = 53 ± 3%; P < 0.05). The antioxidants, apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), and tempol (superoxide dismutase mimetic) normalized impaired relaxation by DNCB in aorta (DNCB Emax = 53 ± 3%, DNCB + tempol Emax = 66 ± 3%; P < 0.05). In addition, DNCB reduced sodium nitroprusside-induced relaxation. DNCB increased soluble guanylyl cyclase (sGC) S-nitrosylation and decreased sGC activity. These data suggest that TrxR regulates vascular relaxation via antioxidant defense and sGC S-nitrosylation. TrxR may be an enzyme to approach for treatment of vascular dysfunction and arterial hypertension.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetophenones / pharmacology
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Acetylcholine / pharmacology
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Animals
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Antioxidants / pharmacology
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / metabolism*
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Auranofin / pharmacology
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Cyclic GMP / metabolism
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Cyclic N-Oxides / pharmacology
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Dinitrochlorobenzene / pharmacology
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Enzyme Inhibitors / pharmacology*
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Guanylate Cyclase / metabolism
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Hydrogen Peroxide / metabolism
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In Vitro Techniques
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Male
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Mice
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Mice, Inbred C57BL
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Nitroprusside / pharmacology
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Oxidative Stress / drug effects*
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Reactive Oxygen Species / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / metabolism
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S-Nitrosothiols / metabolism*
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Soluble Guanylyl Cyclase
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Spin Labels
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Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
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Thioredoxin-Disulfide Reductase / metabolism
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Vasodilation / drug effects*
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Vasodilator Agents / pharmacology
Substances
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3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
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Acetophenones
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Antioxidants
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Cyclic N-Oxides
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Dinitrochlorobenzene
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Enzyme Inhibitors
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Pyrazoles
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Pyridines
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Reactive Oxygen Species
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Receptors, Cytoplasmic and Nuclear
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S-Nitrosothiols
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Spin Labels
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Vasodilator Agents
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Nitroprusside
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Auranofin
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acetovanillone
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Hydrogen Peroxide
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Thioredoxin-Disulfide Reductase
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Guanylate Cyclase
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Soluble Guanylyl Cyclase
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Cyclic GMP
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Acetylcholine
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tempol