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1.
Curr Opin Nephrol Hypertens ; 30(3): 369-376, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33767065

RESUMO

PURPOSE OF REVIEW: : Sarcopenia, defined as decreased muscle mass or function, is prevalent in chronic kidney disease (CKD) increasing the risk of mobility impairment and frailty. CKD leads to metabolic acidosis (MA) and retention of uremic toxins contributing to insulin resistance and impaired muscle mitochondrial energetics. Here we focus on the central role of muscle mitochondrial metabolism in muscle function. RECENT FINDINGS: : Mitochondrial dysfunction underlies muscle wasting and poor physical endurance in CKD. Uremic toxins accumulate in muscle disrupting mitochondrial respiration and enzymes. Changes in mitochondrial quantity, quality, and oxidative capacity contribute to mobility impairment in CKD. Major determinants of muscle mitochondrial function are kidney function, inflammation, and oxidative stress. In CKD, MA is the major determinant of muscle mitochondrial function. Metabolomics reveals defects in pathways linked to mitochondrial energy metabolism and acid-base homeostasis underlying insulin resistance in CKD. SUMMARY: : Decreased mitochondrial capacity and quality control can impair muscle function contributing to decreased physical endurance. MA augments insulin resistance perpetuating the catabolic state underlying muscle wasting in CKD. Further studies are needed to investigate if targeting of MA improves muscle mitochondrial function and insulin resistance translating into meaningful improvements in physical endurance.

2.
Am J Physiol Renal Physiol ; 319(5): F885-F894, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32985237

RESUMO

Patients with end-stage kidney disease on maintenance hemodialysis commonly develop protein-energy wasting, a syndrome characterized by nutritional and metabolic abnormalities. Nutritional supplementation and exercise are recommended to prevent protein-energy wasting. In a 6-mo prospective randomized, open-label, clinical trial, we reported that the combination of resistance exercise and nutritional supplementation does not have an additive effect on lean body mass measured by dual-energy X-ray absorptiometry. To provide more mechanistic data, we performed a secondary analysis where we hypothesized that the combination of nutritional supplementation and resistance exercise would have additive effects on muscle protein accretion by stable isotope protein kinetic experiments, muscle mass by MRI, and mitochondrial content markers in muscle. We found that 6 mo of nutritional supplementation during hemodialysis increased muscle protein net balance [baseline: 2.5 (-17.8, 13.0) µg·100 mL-1·min-1 vs. 6 mo: 43.7 (13.0, 98.5) µg·100 mL-1·min-1, median (interquartile range), P = 0.04] and mid-thigh fat area [baseline: 162.3 (104.7, 226.6) cm2 vs. 6 mo: 181.9 (126.3, 279.2) cm2, median (interquartile range), P = 0.04]. Three months of nutritional supplementation also increased markers of mitochondrial content in muscle. Although the study is underpowered to detected differences, the combination of nutritional supplementation and exercise failed to show further benefit in protein accretion or muscle cross-sectional area. We conclude that long-term nutritional supplementation increases the skeletal muscle anabolic effect, the fat cross-sectional area of the thigh, and markers of mitochondrial content in skeletal muscle.

3.
J Am Soc Nephrol ; 31(11): 2573-2587, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32764136

RESUMO

BACKGROUND: CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-κB mediate the response. METHODS: Subtotal nephrectomy created a mouse model of CKD with BUN >80 mg/dl. Crossing NO66flox/flox with MCK-Cre mice bred muscle-specific NO66 (MCK-NO66) knockout mice. Experiments assessed the effect of removing NO66. RESULTS: Muscle-specific NO66 knockout in mice blocks CKD-induced loss of muscle mass and improves protein synthesis. NO66 suppression of ribosomal biogenesis via demethylase activity is the mechanism behind these responses. In muscle cells, expression of NO66, but not of demethylase-dead mutant NO66, decreased H3K4me3 and H3K36me3 and suppressed pre-rRNA expression. Knocking out NO66 increased the enrichment of H3K4me3 and H3K36me3 on ribosomal DNA. In primary muscle cells and in muscles of mice without NO66, ribosomal RNA, pre-rRNA, and protein synthesis all increased. CONCLUSIONS: CKD suppresses muscle protein synthesis via epigenetic mechanisms that NO66 mediates. Blocking NO66 could suggest strategies that counter CKD-induced abnormal muscle protein catabolism.

4.
Clin J Am Soc Nephrol ; 15(7): 926-936, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32591419

RESUMO

BACKGROUND AND OBJECTIVES: Patients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3-5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission). RESULTS: We found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4-70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4-49.1] seconds) compared with controls (38.9 [32.5-46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48-1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24-0.75] A.U.). CONCLUSIONS: Mitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3-5.

5.
JCI Insight ; 3(16)2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30135309

RESUMO

Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.


Assuntos
Glicemia/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Metaboloma/fisiologia , Insuficiência Renal Crônica/metabolismo , Idoso , Aminoácidos/sangue , Aminoácidos/metabolismo , Glicemia/análise , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Técnica Clamp de Glucose , Voluntários Saudáveis , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia
6.
High Alt Med Biol ; 19(3): 221-231, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29782186

RESUMO

Corante, Noemí, Cecilia Anza-Ramírez, Rómulo Figueroa-Mujíca, José Luis Macarlupú, Gustavo Vizcardo-Galindo, Grzegorz Bilo, Gianfranco Parati, Jorge L. Gamboa, Fabiola León-Velarde, and Francisco C. Villafuerte. Excessive erythrocytosis and cardiovascular risk in Andean highlanders. High Alt Med Biol. 19:221-231, 2018.-Cardiovascular diseases are the main cause of death worldwide. Life under high-altitude (HA) hypoxic conditions is believed to provide highlanders with a natural protection against cardiovascular and metabolic diseases compared with sea-level inhabitants. However, some HA dwellers become intolerant to chronic hypoxia and develop a progressive incapacitating syndrome known as chronic mountain sickness (CMS), characterized by excessive erythrocytosis (EE; Hb ≥21 g/dL in men, Hb ≥19 g/dL in women). Evidence from HA studies suggests that, in addition to CMS typical signs and symptoms, these highlanders may also suffer from metabolic and cardiovascular disorders. Thus, we hypothesize that this syndrome is also associated to the loss of the cardiometabolic protection observed in healthy highlanders (HH), and therefore to a higher cardiovascular risk (CVR). The aim of the present work was to evaluate the association between EE and CVR calculated using the Framingham General CVR Score and between EE and CVR factors in male highlanders. This cross-sectional study included 342 males from Cerro de Pasco, Peru at 4340 m (HH = 209, CMS = 133). Associations were assessed by multiple logistic regressions adjusted for potential confounders (BMI, pulse oxygen saturation and age). The adjusted models show that the odds of high CVR (>20%) in highlanders with EE was 3.63 times the odds in HH (CI 95%:1.22-10.78; p = 0.020), and that EE is associated to hypertension, elevated fasting serum glucose, insulin resistance, and elevated fasting serum triglycerides. Our results suggest that individuals who suffer from EE are at increased risk of developing cardiovascular events compared with their healthy counterparts.


Assuntos
Altitude , Pressão Sanguínea , Doenças Cardiovasculares/epidemiologia , Policitemia/epidemiologia , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Policitemia/fisiopatologia , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
7.
JCI Insight ; 2(22)2017 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-29202452

RESUMO

BACKGROUND: Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients. METHODS: Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin ß1 gene KO CKD mice models. RESULTS: Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease. CONCLUSION: These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation. FUNDING: This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.


Assuntos
Inflamação , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Diálise Renal , Insuficiência Renal Crônica/metabolismo , Adulto , Animais , Biomarcadores , Proteína C-Reativa , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Homeostase , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Cinética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
8.
Psychiatry Res ; 258: 365-373, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28888697

RESUMO

Suicidal behavior is frequently triggered by social crises, such as familial, romantic, social or work-related conflict. A variety of cognitive and social functioning impairments has been associated with suicidal thoughts and acts. One of the precipitating and perpetuating factors of social conflict is the desire for retribution after a perceived offense, even at one's own detriment. We utilized the Ultimatum Game-a behavioral economic task which examines the behavioral response to perceived unfairness-in order to characterize the response to unfairness across the acute suicide risk spectrum. We examined five groups of adult individuals of both genders (n = 204): High- and Low-Lethality recent Suicide Attempters, Suicidal Ideators, Non-Suicidal Depressed Patients; and Healthy Controls. We also measured demographic and clinical variables. Even though all depressed groups showed similar rejection rates in the Ultimatum Game, there was a higher likelihood of rejecting offers in the low stakes condition in all acutely suicidal groups compared with healthy controls. Stake size, offer, education, and gender of the proposer were significantly associated with rejection rates. Acutely suicidal patients may be more vulnerable to adverse interpersonal interactions. Further characterization of social behavior may provide targets for secondary and tertiary prevention for high-risk individuals.


Assuntos
Comportamento Social , Justiça Social , Ideação Suicida , Tentativa de Suicídio/psicologia , Adulto , Estudos de Casos e Controles , Depressão/psicologia , Feminino , Humanos , Relações Interpessoais , Masculino , Tentativa de Suicídio/prevenção & controle
9.
Circ Res ; 121(5): 564-574, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28684630

RESUMO

RATIONALE: Clinical studies have shown that Sirt3 (Sirtuin 3) expression declines by 40% by 65 years of age paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 because of increased NADH (nicotinamide adenine dinucleotide, reduced form) and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) because of hyperacetylation. OBJECTIVE: In this study, we examined whether the loss of Sirt3 activity increases vascular oxidative stress because of SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension. METHODS AND RESULTS: Hypertension was markedly increased in Sirt3-knockout (Sirt3-/-) and SOD2-depleted (SOD2+/-) mice in response to low dose of angiotensin II (0.3 mg/kg per day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O2· -, and diminished endothelial nitric oxide. Angiotensin II-induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2, and reduced SOD2 activity. Scavenging of mitochondrial H2O2 in mCAT mice expressing mitochondria-targeted catalase prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H2O2 scavenger, mitochondria-targeted hydrogen peroxide scavenger ebselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation, and reduced blood pressure in wild-type but not in Sirt3-/- mice, whereas an SOD2 mimetic, (2-[2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino]-2-oxoethyl) triphenylphosphonium (mitoTEMPO), reduced blood pressure and improved vasorelaxation both in Sirt3-/- and wild-type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels, whereas SOD2 expression was not affected. CONCLUSIONS: Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.


Assuntos
Hipertensão/metabolismo , Estresse Oxidativo/fisiologia , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Acetilação , Animais , Células Cultivadas , Humanos , Hipertensão/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sirtuína 3/genética , Superóxido Dismutase/genética
10.
Diabetologia ; 60(6): 1066-1075, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28352940

RESUMO

AIMS/HYPOTHESIS: Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. METHODS: We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 -/- mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. RESULTS: Cyp2c44 -/- mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg-1 min-1 in WT and Cyp2c44 -/- mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 -/- mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 µmol 100 g-1 min-1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44 -/- vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. CONCLUSIONS/INTERPRETATION: CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Ilhotas Pancreáticas/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/genética , Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Masculino , Artérias Mesentéricas/metabolismo , Camundongos
11.
Physiol Rep ; 4(9)2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27162261

RESUMO

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.


Assuntos
Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica/metabolismo , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/patologia
12.
Pharmacol Res Perspect ; 4(2): e00221, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27069632

RESUMO

A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti-thrombotic prostacyclin. This study tested the hypothesis that extended-release aspirin (NHP-554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate-release aspirin (ASA). Thirty-six healthy subjects were randomized to NHP-554C or ASA groups. Within each group, subjects were randomized to 5-day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2-week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11-dehydro-thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3-dinor-6-keto-PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP-554C 81 mg/d and 162.5 mg/d reduced 11-dehydro-thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3-dinor-6-keto-PGF1α 13.4% and 18.5%, respectively. NHP-554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP-554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3-dinor-6-keto-PGF1α. Nevertheless, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-PGF1α responses to bradykinin were statistically similar during ASA and NHP-554C. In conclusion, at doses of 81 and 162.5 mg/d immediate- and extended-release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin-stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP-554C.

13.
J Clin Endocrinol Metab ; 100(12): 4533-40, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26580240

RESUMO

CONTEXT: Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance. OBJECTIVE: The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function. DESIGN: This was a randomized, double-blind, placebo-controlled study. SETTING: This trial was conducted at Vanderbilt Clinical Research Center. PARTICIPANTS: Participants included overweight individuals with prediabetes. INTERVENTIONS: Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment. MAIN OUTCOME MEASURES: The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion. RESULT: Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per µU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per µU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 µg/mg Cr. This effect persisted 3 months after sildenafil discontinuation. CONCLUSIONS: Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.


Assuntos
Resistência à Insulina , Inibidores da Fosfodiesterase 5/uso terapêutico , Estado Pré-Diabético/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Adulto , Albuminúria/prevenção & controle , Método Duplo-Cego , Endotélio Vascular/efeitos dos fármacos , Feminino , Fibrinólise/efeitos dos fármacos , Glucose/farmacologia , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Hemodinâmica/efeitos dos fármacos , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Estado Pré-Diabético/fisiopatologia
14.
BMC Nephrol ; 16: 167, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26494370

RESUMO

BACKGROUND: Endothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) contributes to endothelial dysfunction in ESRD. In the general population, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease ADMA levels, but no study has compared the effect of these drugs in patients with ESRD on maintenance hemodialysis (MHD). METHODS: We evaluated the effect of 1-week treatment with ramipril (5 mg/d), valsartan (160 mg/d), and placebo on ADMA levels in 15 patients on MHD in a double-blind, placebo-controlled, three x three cross-over study. RESULTS: We found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (p < 0.001 compared to both, placebo and valsartan). Ramipril did not increase ADMA levels in a study of patients without ESRD, suggesting that factors related to ESRD or hemodialysis contribute to the ACE inhibitor-induced increase in ADMA. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. We therefore evaluated the effect of bradykinin on ADMA production in A549 cells; a cell line that expresses BK receptors. Incubation with BK increased intracellular ADMA concentration through BK B2-receptor stimulation. CONCLUSION: These data indicate that short-term ACE inhibition increases ADMA in patients on MHD whereas ARBs do not. In vitro studies further suggest that this may occur through BK-mediated increase in ADMA production during ACE inhibition. TRIAL REGISTRATION: Clinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Arginina/análogos & derivados , Falência Renal Crônica/sangue , Ramipril/farmacologia , Diálise Renal , Valsartana/farmacologia , Arginina/sangue , Arginina/efeitos dos fármacos , Arginina/metabolismo , Bradicinina/farmacologia , Linhagem Celular , Estudos Cross-Over , Método Duplo-Cego , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade
15.
PLoS One ; 9(9): e108733, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25259712

RESUMO

BACKGROUND: Prosocial behaviors are essential to the ability to relate to others. Women typically display greater prosocial behavior than men. The impact of depression on prosocial behaviors and how gender interacts with those effects are not fully understood. We explored the role of gender in the potential effects of depression on prosocial behavior. METHODS: We examined prosocial behaviors using a modified version of the Trust Game in a clinical population and community controls. Study participants were characterized on the severity of depression and anxiety, presence of suicidal ideation, history of childhood trauma, recent stressful life events, and impulsivity. We correlated behavioral outcomes with gender and clinical variables using analysis of variance and multiple regression analysis. RESULTS: The 89 participants comprised four study groups: depressed women, depressed men, healthy women and healthy men (n = 16-36). Depressed men exhibited reciprocity more frequently than healthy men. Depression induced an inversion of the gender-specific pattern of self-centered behavior. Suicidal ideation was associated with increased reciprocity behavior in both genders, and enhancement of the effect of depression on gender-specific self-centered behavior. CONCLUSIONS: Depression, particularly suicidal ideation, is associated with reversal of gender-specific patterns of prosocial behavior, suggesting abnormalities in sexual hormones regulation. This explanation is supported by known abnormalities in the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes found in depression.


Assuntos
Depressão/psicologia , Caracteres Sexuais , Comportamento Social , Ideação Suicida , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Depressão/diagnóstico , Feminino , Jogos Experimentais , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Estresse Psicológico/psicologia , Adulto Jovem
16.
Genome Biol ; 15(2): R36, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24555826

RESUMO

BACKGROUND: Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited. RESULTS: We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3. CONCLUSIONS: Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection.


Assuntos
Aclimatação/genética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hipóxia/genética , Altitude , Animais , Cromossomos Humanos Par 19 , Drosophila/genética , Etiópia , Grupos Étnicos , Genética Populacional , Genoma Humano , Humanos , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Homologia de Sequência de Aminoácidos
17.
Am J Hum Genet ; 93(3): 452-62, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23954164

RESUMO

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.


Assuntos
Doença da Altitude/genética , Genoma Humano/genética , Análise de Sequência de DNA , Adulto , Animais , Doença Crônica , Regulação para Baixo/genética , Drosophila melanogaster/genética , Feminino , Estudos de Associação Genética , Genética Populacional , Genômica , Humanos , Hipóxia/genética , Masculino , Peru , Reprodutibilidade dos Testes , Análise de Sobrevida
18.
J Am Soc Nephrol ; 23(2): 334-42, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22158433

RESUMO

Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, double-blind, placebo-controlled 3×3 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1ß concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P<0.01 for each compared with placebo). Valsartan increased F(2)-isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P<0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inflamação/prevenção & controle , Ramipril/uso terapêutico , Diálise Renal/efeitos adversos , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Coagulação Sanguínea/efeitos dos fármacos , Ligante de CD40/sangue , Estudos Cross-Over , Citocinas/biossíntese , Método Duplo-Cego , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Renina/sangue , Valina/uso terapêutico , Valsartana
19.
Pflugers Arch ; 463(2): 327-38, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22113781

RESUMO

Skeletal muscle adaptation to chronic hypoxia includes loss of oxidative capacity and decrease in fiber size. However, the diaphragm may adapt differently since its activity increases in response to hypoxia. Thus, we hypothesized that chronic hypoxia would not affect endurance, mitochondrial function, or fiber size in the mouse diaphragm. Adult male mice were kept in normoxia (control) or hypoxia (hypoxia, FIO(2) = 10%) for 4 weeks. After that time, muscles were collected for histological, biochemical, and functional analyses. Hypoxia soleus muscles fatigued faster (fatigue index higher in control, 21.5 ± 2.6% vs. 13.4 ± 2.4%, p < 0.05), but there was no difference between control and hypoxia diaphragm bundles. Mean fiber cross-sectional area was unchanged in hypoxia limb muscles, but it was 25% smaller in diaphragm (p < 0.001). Ratio of capillary length contact to fiber perimeter was significantly higher in hypoxia diaphragm (28.6 ± 1.2 vs. 49.3 ± 1.4, control and hypoxia, p < 0.001). Mitochondrial respiration rates in hypoxia limb muscles were lower: state 2 decreased 19%, state 3 31%, and state 4 18% vs. control, p < 0.05 for all comparisons. There were similar changes in hypoxia diaphragm: state 3 decreased 29% and state 4 17%, p < 0.05. After 4 weeks of hypoxia, limb muscle mitochondria had lower content of complex IV (cytochrome c oxidase), while diaphragm mitochondria had higher content of complexes IV and V (F (1)/F (0) ATP synthase) and less uncoupling protein 3 (UCP-3). These data demonstrate that diaphragm retains its endurance during chronic hypoxia, apparently due to a combination of morphometric changes and optimization of mitochondrial energy production.


Assuntos
Hipóxia/fisiopatologia , Extremidade Inferior/fisiologia , Mitocôndrias Musculares/fisiologia , Força Muscular/fisiologia , Resistência Física/fisiologia , Músculos Respiratórios/fisiologia , Extremidade Superior/fisiologia , Animais , Diafragma/metabolismo , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Modelos Animais , Fadiga Muscular/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Consumo de Oxigênio/fisiologia , Fatores de Tempo , Proteína Desacopladora 3
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