Differential regulation of thioredoxin and NAD(P)H oxidase by angiotensin II in male and female mice

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ObjectiveWe hypothesized that downregulation of the antioxidant thioredoxin system contributes to oxidative stress in angiotensin II-induced hypertension. As oestrogen may protect against oxidative stress, we also evaluated whether the thioredoxin system, particularly in the heart, is differentially regulated between females and males.ResultsC57Bl/6 male and intact or ovariectomized female mice were infused with angiotensin II (400 ng/kg per minute for 2 weeks). Systolic blood pressure (SBP) was increased by angiotensin II in both groups week 1 and increased further in males versus females in week 2. Angiotensin II increased SBP from 112 ± 6 to 143 ± 9 mmHg in ovariectomized mice. Basal cardiac thioredoxin expression and reductase activity were significantly higher (two to threefold) in females versus males. Angiotensin II increased thioredoxin expression (approximately threefold), thioredoxin reductase activity, nicotinamide adenine dinucleotide phosphate, reduced form (NAD(P)H) oxidase activity and plasma thiobarbituric acid-reducing substances in males but not in females. Angiotensin II increased thioredoxin expression and NAD(P)H oxidase activity in ovariectomized versus control mice. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE/Ref-1) activation, which interacts with thioredoxin to activate inflammatory transcription factors, was increased by angiotensin II only in males.ConclusionThese results demonstrate sex dimorphism with respect to thioredoxin, oxidative stress and inflammation, and suggest the differential regulation of blood pressure, the cardiac thioredoxin system and NAD(P)H oxidase activity by angiotensin II in male and female mice. Whereas angiotensin II increases the activity of thioredoxin reductase and APE/Ref-1, enhances oxidative stress, and amplifies blood pressure elevation in males, it has little effect in females. Such differences may partly relate to the protective actions of oestrogens.

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