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Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide.

ABSTRACT: Nitric oxide ((•)NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2(•-)) regulates cellular proliferation, and (•)NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that (•)NO differentially regulates SOD-1 based on sex.Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2(•-) levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±(•)NO treatment and SOD-1 protein levels were examined by Western blot.In vitro, male VSMC have higher O2(•-) levels and lower SOD - 1 activity at baseline compared to female VSMC (P < 0.05). (•)NO decreased O2(•-) levels and increased SOD - 1 activity in male (P<0.05) but not female VSMC. (•)NO also increased sod- 1 gene expression and SOD - 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but (•)NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females.Our results provide evidence that regulation of the redox environment at baseline and following exposure to (•)NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which (•)NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents.

SUBMITTER: Morales RC

PROVIDER: S-EPMC4803798 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide.

Morales Rommel C RC Bahnson Edward S M ES Havelka George E GE Cantu-Medellin Nadiezhda N Kelley Eric E EE Kibbe Melina R MR

Redox biology 20150113

<h4>Background</h4>Nitric oxide ((•)NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2(•-)) regulates cellular proliferation, and (•)NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that (•)NO differentially regulates SOD-1 based on sex.<h4>Materials and methods</h4>Male and female vascular smooth muscle cells (VSMC) were harvested from the aor ...[more]

PMID: 25617803

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Project description:BACKGROUND:Nutrition with ammonium (NH4+) can enhance the drought tolerance of rice seedlings in comparison to nutrition with nitrate (NO3-). However, there are still no detailed studies investigating the response of nitric oxide (NO) to the different nitrogen nutrition and water regimes. To study the intrinsic mechanism underpinning this relationship, the time-dependent production of NO and its protective role in the antioxidant defense system of NH4+- or NO3--supplied rice seedlings were studied under water stress. RESULTS:An early NO burst was induced by 3?h of water stress in the roots of seedlings subjected to NH4+ treatment, but this phenomenon was not observed under NO3- treatment. Root oxidative damage induced by water stress was significantly higher for treatment with NO3- than with NH4+ due to reactive oxygen species (ROS) accumulation in the former. Inducing NO production by applying the NO donor 3?h after NO3- treatment alleviated the oxidative damage, while inhibiting the early NO burst by applying the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) increased root oxidative damage in NH4+ treatment. Application of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester(L-NAME) completely suppressed NO synthesis in roots 3?h after NH4+ treatment and aggravated water stress-induced oxidative damage. Therefore, the aggravation of oxidative damage by L-NAME might have resulted from changes in the NOS-mediated early NO burst. Water stress also increased the activity of root antioxidant enzymes (catalase, superoxide dismutase, and ascorbate peroxidase). These were further induced by the NO donor but repressed by the NO scavenger and NOS inhibitor in NH4+-treated roots. CONCLUSION:These findings demonstrate that the NOS-mediated early NO burst plays an important role in alleviating oxidative damage induced by water stress by enhancing the antioxidant defenses in roots supplemented with NH4+.

Project description:Aims/introductionThe role of the renal nitric oxide (NO) system in the pathophysiology of diabetic nephropathy constitutes a very challenging and fertile field for future investigation. The purpose of the present study was to investigate whether NO donors can attenuate diabetic renal fibrosis and apoptosis through modulating oxidative-and nitrosative-stress, and Wnt signaling using in vivo diabetic models.Materials and methodsDiabetic rat was induced by a single intraperitoneal injection of streptozotocin. Rats in each group were intraperitoneally given 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (1 U/kg/day) and vehicle for 28 and 56 consecutive days. Expression of the oxidative-and nitrosative-stress, and Wnt signaling components were examined in kidneys from diabetic animals by quantitative reverse transcription polymerase chain reaction, western blot analysis and immunohistochemical staining.ResultsNO donor treatment significantly reduced the ratio of kidney weight to bodyweight and proteinuria. This treatment also significantly restored the suppressive effect of diabetes on urinary NO2 + NO3 levels. Immunohistochemistry showed that NO donor treatment significantly reduced transforming growth factor (TGF)-β1, fibronectin, cleaved caspase-3 and triphosphate-biotin nick end-labeling expression in the glomeruli of diabetic rats. We found that diabetes promoted 8-hydroxy-2'-deoxyguanosine, and peroxynitrite expression coincided with reduced endothelial NO synthase expression in glomeruli. Interestingly, NO donor treatment completely removed oxidative stress and nitrosative stress, and restored endothelial NO synthase expression in diabetic renal glomeruli. Immunohistomorphometry results showed that NO donor treatment significantly restored suppressed Wnt5a expression and β-catenin immunoreactivities in glomeruli. Based on laser-captured microdissection for quantitative reverse transcription polymerase chain reaction, diabetes significantly increased TGF-β1, and fibronectin expression coincided with depressed Wnt5a expression. NO donor treatment reduced TGF-β1, fibronectin activation, and the suppressing effect of diabetes on Wnt5a and β-catenin expression in renal glomeruli.ConclusionsNO donor treatment alleviates extracellular matrix accumulation and apoptosis in diabetic nephropathy in vivo by not only preventing the diabetes-mediated oxidative and nitrostative stress, but also restoring downregulation of endothelial NO synthase expression and Wnt/β-catenin signaling. These findings suggest that modulation of NO is a viable alternative strategy for rescuing diabetic renal injury.

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Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide.

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Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide.

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