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1.
Nitric Oxide ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32032718

RESUMO

BACKGROUND/PURPOSE: Unhealthy dietary habits contribute to the increasing incidence of metabolic syndrome and type 2 diabetes (T2D), which is accompanied by oxidative stress, compromised nitric oxide (NO) bioavailability and increased cardiovascular risk. Apart from lifestyle changes, biguanides such as metformin are the first-line pharmacological treatment for T2D. Favourable cardiometabolic effects have been demonstrated following dietary nitrate supplementation to boost the nitrate-nitrite-NO pathway. Here we aim to compare the therapeutic value of inorganic nitrate and metformin alone and their combination in a model of cardiometabolic disease. EXPERIMENTAL APPROACH: Mice were fed control or high fat diet (HFD) for 7 weeks in combination with the NO synthase (NOS) inhibitor l-NAME to induce metabolic syndrome. Simultaneously, the mice were treated with vehicle, inorganic nitrate, metformin or a combination of nitrate and metformin in (drinking water). Cardiometabolic functions were assessed in vivo and tissues were collected/processed for analyses. KEY RESULTS: HFD + L-NAME was associated with cardiometabolic dysfunction, compared with controls, as evident from elevated blood pressure, endothelial dysfunction, impaired insulin sensitivity and compromised glucose clearance as well as liver steatosis. Both nitrate and metformin improved insulin/glucose homeostasis, whereas only nitrate had favourable effects on cardiovascular function and steatosis. Mechanistically, metformin and nitrate improved AMPK signalling, whereas only nitrate attenuated oxidative stress. Combination of nitrate and metformin reduced HbA1c and trended to further increase AMPK activation. CONCLUSION/IMPLICATIONS: Nitrate and metformin had equipotent metabolic effects, while nitrate was superior regarding protection against cardiovascular dysfunction and liver steatosis. If reproduced in future clinical trials, these findings may have implications for novel nutrition-based strategies against metabolic syndrome, T2D and associated complications.

4.
Free Radic Biol Med ; 145: 342-348, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31600544

RESUMO

Nitric oxide (NO) is a key signalling molecule in the regulation of cardiometabolic function and impaired bioactivity is considered to play an important role in the onset and progression of cardiovascular and metabolic disease. Research has revealed an alternative NO-generating pathway, independent of NO synthase (NOS), in which the inorganic anions nitrate (NO3-) and nitrite (NO2-) are serially reduced to form NO. This work specifically aimed at investigating the role of commensal bacteria in bioactivation of dietary nitrate and its protective effects in a model of cardiovascular and metabolic disease. In a two-hit model, germ-free and conventional male mice were fed a western diet and the NOS inhibitor l-NAME in combination with sodium nitrate (NaNO3) or placebo (NaCl) in the drinking water. Cardiometabolic parameters including blood pressure, glucose tolerance and body composition were measured after six weeks treatment. Mice in both placebo groups showed increased body weight and fat mass, reduced lean mass, impaired glucose tolerance and elevated blood pressure. In conventional mice, nitrate treatment partly prevented the cardiometabolic disturbances induced by a western diet and l-NAME. In contrast, in germ-free mice nitrate had no such beneficial effects. In separate cardiovascular experiments, using conventional and germ-free animals, we assessed NO-like signalling downstream of nitrate by administration of sodium nitrite (NaNO2) via gavage. In this acute experimental setting, nitrite lowered blood pressure to a similar degree in both groups. Likewise, isolated vessels from germ-free mice robustly dilated in response to the NO donor sodium nitroprusside. In conclusion, our findings demonstrate the obligatory role of host-microbiota in bioactivation of dietary nitrate, thus contributing to its favourable cardiometabolic effects.

5.
FEBS Lett ; 593(14): 1799-1806, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31125428

RESUMO

Glutaredoxins (Grx) are involved in many reactions including defense against oxidative stress. However, the role of the Grx system under nitrosative stress has barely been investigated. In this study, we found that human Grxs denitrosylated both low and high molecular weight S-nitrosothiols. Some S-nitrosylated proteins, stable in the presence of a physiological concentration of glutathione (GSH), were denitrosylated by Grxs. Caspase 3 and cathepsin B were identified as substrates of Grx1-catalysed denitrosylation. In addition, mono-thiol Grxs, such as Grx5, exhibited denitrosylase activity coupled with GSH via a monothiol mechanism. Our study demonstrates the ability of Grxs to act as S-denitrosylases and pinpoint a new mechanism for denitrosylation.

6.
Circulation ; 139(23): 2654-2663, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905171

RESUMO

BACKGROUND: Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin ß chain (ß93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection. METHODS: To test this hypothesis, we used RBCs from mice in which the ß93 cysteine had been replaced with alanine (ß93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity. RESULTS: In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (ß93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with ß93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in ß93C and ß93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between ß93C and ß93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in ß93C and ß93A mice. CONCLUSIONS: RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the ß93 cysteine of Hb.

7.
Hypertension ; 73(4): 839-848, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712424

RESUMO

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT1Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT1Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/terapia , Nitratos/farmacologia , Sistema Nervoso Simpático/fisiopatologia , Angiotensina II/toxicidade , Animais , Barorreflexo/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
8.
Proc Natl Acad Sci U S A ; 116(1): 217-226, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30559212

RESUMO

Advanced age and unhealthy dietary habits contribute to the increasing incidence of obesity and type 2 diabetes. These metabolic disorders, which are often accompanied by oxidative stress and compromised nitric oxide (NO) signaling, increase the risk of adverse cardiovascular complications and development of fatty liver disease. Here, we investigated the therapeutic effects of dietary nitrate, which is found in high levels in green leafy vegetables, on liver steatosis associated with metabolic syndrome. Dietary nitrate fuels a nitrate-nitrite-NO signaling pathway, which prevented many features of metabolic syndrome and liver steatosis that developed in mice fed a high-fat diet, with or without combination with an inhibitor of NOS (l-NAME). These favorable effects of nitrate were absent in germ-free mice, demonstrating the central importance of host microbiota in bioactivation of nitrate. In a human liver cell line (HepG2) and in a validated hepatic 3D model with primary human hepatocyte spheroids, nitrite treatment reduced the degree of metabolically induced steatosis (i.e., high glucose, insulin, and free fatty acids), as well as drug-induced steatosis (i.e., amiodarone). Mechanistically, the salutary metabolic effects of nitrate and nitrite can be ascribed to nitrite-derived formation of NO species and activation of soluble guanylyl cyclase, where xanthine oxidoreductase is proposed to mediate the reduction of nitrite. Boosting this nitrate-nitrite-NO pathway results in attenuation of NADPH oxidase-derived oxidative stress and stimulation of AMP-activated protein kinase and downstream signaling pathways regulating lipogenesis, fatty acid oxidation, and glucose homeostasis. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against liver steatosis associated with metabolic dysfunction.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fígado Gorduroso/prevenção & controle , NADPH Oxidases/antagonistas & inibidores , Nitratos/farmacologia , Nitritos/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/administração & dosagem , Óxido Nítrico/metabolismo , Nitritos/administração & dosagem
10.
J Card Fail ; 24(10): 640-653, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30244181

RESUMO

BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.


Assuntos
Beta vulgaris/química , Suplementos Nutricionais , Sucos de Frutas e Vegetais , Hipertensão Pulmonar/dietoterapia , Nitratos/análise , Pressão Propulsora Pulmonar/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estudos Prospectivos
11.
JACC Basic Transl Sci ; 3(4): 450-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175269

RESUMO

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

12.
J Am Coll Cardiol ; 72(7): 769-780, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30092954

RESUMO

BACKGROUND: Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM. OBJECTIVES: The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase. METHODS: RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies. RESULTS: Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism. CONCLUSIONS: This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.


Assuntos
Arginase/biossíntese , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Endotélio Vascular/enzimologia , Eritrócitos/enzimologia , Idoso , Animais , Arginase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia
13.
Nitric Oxide ; 80: 37-44, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30099096

RESUMO

Chronic hypertension in pregnancy is associated with significant adverse pregnancy outcomes, increasing the risk of pre-eclampsia, fetal growth restriction and preterm birth. Dietary nitrate, abundant in green leafy vegetables and beetroot, is reduced in vivo to nitrite and subsequently nitric oxide, and has been demonstrated to lower blood pressure, improve vascular compliance and enhance blood flow in non-pregnant humans and animals. The primary aims of this study were to determine the acceptability and efficacy of dietary nitrate supplementation, in the form of beetroot juice, to lower blood pressure in hypertensive pregnant women. In this double-blind, placebo-controlled feasibility trial, 40 pregnant women received either daily nitrate supplementation (70 mL beetroot juice, n = 20) or placebo (70 mL nitrate-depleted beetroot juice, n = 20) for 8 days. Blood pressure, cardiovascular function and uteroplacental blood flow was assessed at baseline and following acute (3 h) and prolonged (8 days) supplementation. Plasma and salivary samples were collected for analysis of nitrate and nitrite concentrations and acceptability of this dietary intervention was assessed based on questionnaire feedback. Dietary nitrate significantly increased plasma and salivary nitrate/nitrite concentrations compared with placebo juice (p < 0.001), with marked variation between women. Compared with placebo, there was no overall reduction in blood pressure in the nitrate-treated group; however there was a highly significant correlation between changes in plasma nitrite concentrations and changes in diastolic blood pressure in the nitrate-treated arm only (r = -0.6481; p = 0.0042). Beetroot juice supplementation was an acceptable dietary intervention to 97% of women. This trial confirms acceptability and potential efficacy of dietary nitrate supplementation in pregnant women. Conversion of nitrate to nitrite critically involves oral bacterial nitrate reductase activities. We speculate that differences in efficacy of nitrate supplementation relate to differences in the oral microbiome, which will be investigated in future studies.


Assuntos
Beta vulgaris , Pressão Sanguínea/efeitos dos fármacos , Sucos de Frutas e Vegetais , Hipertensão Induzida pela Gravidez/dietoterapia , Nitratos/administração & dosagem , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Nitratos/sangue , Placebos , Gravidez , Resultado do Tratamento
14.
Cell Metab ; 28(1): 9-22, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29972800

RESUMO

Nitric oxide (NO), generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored. The inorganic anions nitrate (NO3-) and nitrite (NO2-), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues. The described cardio-metabolic effects of dietary nitrate from experimental and clinical studies include lowering of blood pressure, improved endothelial function, increased exercise performance, and reversal of metabolic syndrome, as well as antidiabetic effects. The mechanisms underlying the salutary metabolic effects of nitrate are being revealed and include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress. Here we review the recent advances in the nitrate-nitrite-NO pathway, focusing on metabolic effects in health and disease.


Assuntos
Sistema Cardiovascular/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome Metabólica/metabolismo , Mitocôndrias/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Animais , Diabetes Mellitus Tipo 2/dietoterapia , Dieta , Humanos , Síndrome Metabólica/dietoterapia , Camundongos , Estresse Oxidativo , Ratos
15.
Redox Biol ; 15: 182-191, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29268201

RESUMO

RATIONALE: Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP). METHODS: A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition. RESULTS: NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion. CONCLUSION: Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.


Assuntos
Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Óxido Nítrico/metabolismo , Nitrocompostos/administração & dosagem , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Rim/metabolismo , Rim/patologia , Masculino , Óxido Nítrico Sintase/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos Dahl/genética , Xantina Desidrogenase/genética , Xantina Desidrogenase/metabolismo
16.
Redox Biol ; 13: 320-330, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28623824

RESUMO

Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0mmol/kg/day) or standard chow for two weeks prior to 30min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1ß, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Nitratos/uso terapêutico , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Células Cultivadas , Suplementos Nutricionais , Interleucina-6/genética , Rim/irrigação sanguínea , Ativação de Macrófagos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/administração & dosagem , Nitratos/farmacologia , Superóxidos/metabolismo
17.
Stroke ; 48(7): 1724-1729, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28596448

RESUMO

BACKGROUND AND PURPOSE: A short-term increase in dietary nitrate (NO3-) improves markers of vascular health via formation of nitric oxide and other bioactive nitrogen oxides. Whether this translates into long-term vascular disease risk reduction has yet to be examined. We investigated the association of vegetable-derived nitrate intake with common carotid artery intima-media thickness (CCA-IMT), plaque severity, and ischemic cerebrovascular disease events in elderly women (n=1226). METHODS: Vegetable nitrate intake, lifestyle factors, and cardiovascular disease risk factors were determined at baseline (1998). CCA-IMT and plaque severity were measured using B-mode carotid ultrasound (2001). Complete ischemic cerebrovascular disease hospitalizations or deaths (events) over 14.5 years (15 032 person-years of follow-up) were obtained from the West Australian Data Linkage System. RESULTS: Higher vegetable nitrate intake was associated with a lower maximum CCA-IMT (B=-0.015, P=0.002) and lower mean CCA-IMT (B=-0.012, P=0.006). This relationship remained significant after adjustment for lifestyle and cardiovascular risk factors (P≤0.01). Vegetable nitrate intake was not a predictor of plaque severity. In total 186 (15%) women experienced an ischemic cerebrovascular disease event. For every 1 SD (29 mg/d) higher intake of vegetable nitrate, there was an associated 17% lower risk of 14.5-year ischemic cerebrovascular disease events in both unadjusted and fully adjusted models (P=0.02). CONCLUSIONS: Independent of other risk factors, higher vegetable nitrate was associated with a lower CCA-IMT and a lower risk of an ischemic cerebrovascular disease event.


Assuntos
Doenças das Artérias Carótidas/dietoterapia , Doenças das Artérias Carótidas/epidemiologia , Transtornos Cerebrovasculares/dietoterapia , Transtornos Cerebrovasculares/epidemiologia , Nitratos/administração & dosagem , Verduras , Idoso , Doenças das Artérias Carótidas/metabolismo , Espessura Intima-Media Carotídea/tendências , Transtornos Cerebrovasculares/metabolismo , Registros de Dieta , Feminino , Hospitalização/tendências , Humanos , Estilo de Vida , Nitratos/metabolismo , Inquéritos e Questionários/normas , Verduras/metabolismo , Austrália Ocidental/epidemiologia
18.
Redox Biol ; 13: 163-169, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28578274

RESUMO

In this report, we describe the synthesis and characterization of 1,3-bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries.


Assuntos
Óxido Nítrico/metabolismo , Nitrocompostos/síntese química , Vasodilatadores/síntese química , Xantina Desidrogenase/metabolismo , Animais , Espectroscopia de Ressonância de Spin Eletrônica , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular , Óxido Nítrico/química , Nitrocompostos/química , Nitrocompostos/farmacologia , Ratos , Vasodilatadores/química , Vasodilatadores/farmacologia , Xantina Desidrogenase/química
19.
Acta Obstet Gynecol Scand ; 96(3): 295-301, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28052314

RESUMO

INTRODUCTION: Recurrent vulvovaginal candidiasis is defined as having three to four episodes per year and causes substantial suffering. Little is known about the mechanisms leading to relapses in otherwise healthy women. Nitric oxide is part of the nonspecific host defense and is increased during inflammation. Nitric oxide levels were measured and the expression of inducible nitric oxide synthase was analyzed in the vagina during an acute episode of recurrent vulvovaginal candidiasis and after treatment with fluconazole. MATERIAL AND METHODS: Twenty-eight women with symptoms of recurrent vulvovaginal candidiasis were enrolled together with 31 healthy controls. Nitric oxide was measured with an air-filled 25-mL silicon catheter balloon incubated in the vagina for five minutes and then analyzed by chemiluminescence technique. Vaginal biopsies were analyzed for the expression of inducible nitric oxide synthase. Symptoms and clinical findings were surveyed using a scoring system. The measurements and biopsies were repeated in patients after six weeks of fluconazole treatment. RESULTS: Nitric oxide levels were increased during acute infection (median 352 ppb) compared with controls (median 6 ppb), p < 0.0001. The levels decreased after treatment (median 18 ppb) but were still higher than in controls. Increased expression of inducible nitric oxide synthase was observed in the epithelial basal layer in patients before and after treatment compared with controls. Before treatment, there were positive correlations between nitric oxide and symptom (rs  = 0.644) and examination scores (rs  = 0.677), p < 0.001. CONCLUSIONS: Nitric oxide is significantly elevated in patients with recurrent vulvovaginal candidiasis during acute episodes of infection and decreases after antifungal treatment. The results illustrate the pronounced inflammatory response in recurrent vulvovaginal candidiasis correlating to symptoms of pain and discomfort.


Assuntos
Candidíase Vulvovaginal/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Adolescente , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Fluconazol/administração & dosagem , Fluconazol/uso terapêutico , Humanos , Recidiva , Inquéritos e Questionários , Adulto Jovem
20.
Free Radic Biol Med ; 105: 48-67, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27989792

RESUMO

Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors.


Assuntos
Doenças Cardiovasculares/microbiologia , Microbiota , Boca/microbiologia , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Ácidos Graxos/metabolismo , Humanos , Circulação Pulmonar , Transdução de Sinais
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