RESUMEN

BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR). METHODS: Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn. RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *# nmol/g tissue; * p < 0.05 vs S, # p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups. CONCLUSION: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.

Asunto(s)

Acetilcisteína , Hipertensión , NADPH Oxidasas , Estrés Oxidativo , Ratas Endogámicas SHR , Remodelación Ventricular , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Acetilcisteína/farmacología , Remodelación Ventricular/efectos de los fármacos , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , NADPH Oxidasas/metabolismo , NADPH Oxidasas/genética , Ratas , Antioxidantes/farmacología , Condicionamiento Físico Animal , Modelos Animales de Enfermedad , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , NADPH Oxidasa 4/metabolismo , NADPH Oxidasa 4/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Miocardio/metabolismo , Miocardio/patología , Peróxidos Lipídicos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Suplementos Dietéticos , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Hipertrofia Ventricular Izquierda/metabolismo

RESUMEN

High levels of testosterone (Testo) are associated with cardiovascular risk by increasing reactive oxygen species (ROS) formation. NADPH oxidases (NOX) are the major source of ROS in the vasculature of cardiovascular diseases. NOX4 is a unique isotype, which produces hydrogen peroxide (H2O2), and its participation in cardiovascular biology is controversial. So far, it is unclear whether NOX4 protects from Testo-induced endothelial injury. Thus, we hypothesized that supraphysiological levels of Testo induce endothelial NOX4 expression to attenuate endothelial injury. Human mesenteric vascular endothelial cells (HMECs) and human umbilical vein endothelial cells (HUVEC) were treated with Testo (10-7 M) with or without a NOX4 inhibitor [GLX351322 (10-4 M)] or NOX4 siRNA. In vivo, 10-wk-old C57Bl/6J male mice were treated with Testo (10 mg/kg) for 30 days to study endothelial function. Testo increased mRNA and protein levels of NOX4 in HMECs and HUVECs. Testo increased superoxide anion (O2-) and H2O2 production, which were abolished by NOX1 and NOX4 inhibition, respectively. Testo also attenuated bradykinin-induced NO production, which was further impaired by NOX4 inhibition. In vivo, Testo decreased H2O2 production in aortic segments and triggered endothelial dysfunction [decreased relaxation to acetylcholine (ACh)], which was further impaired by GLX351322 and by a superoxide dismutase and catalase mimetic (EUK134). Finally, Testo led to a dysregulated endothelial cell migration, which was exacerbated by GLX351322. These data indicate that supraphysiological levels of Testo increase the endothelial expression and activity of NOX4 to counterbalance the deleterious effects caused by Testo in endothelial function.NEW & NOTEWORTHY By inducing ROS formation, high levels of testosterone play a major role in the pathogenesis of cardiovascular disease. NOXs are the major sources of ROS in the vasculature of cardiovascular diseases. Herein, we describe a novel compensatory mechanism by showing that NOX4 is a protective oxidant enzyme and counterbalances the deleterious effects of testosterone in endothelial cells by modulating hydrogen peroxide formation.

Asunto(s)

Movimiento Celular , Endotelio Vascular , Células Endoteliales de la Vena Umbilical Humana , Peróxido de Hidrógeno , Ratones Endogámicos C57BL , NADPH Oxidasa 4 , Testosterona , Animales , Humanos , Masculino , Ratones , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , NADPH Oxidasa 4/metabolismo , NADPH Oxidasa 4/genética , Especies Reactivas de Oxígeno/metabolismo , Testosterona/farmacología , Testosterona/metabolismo

RESUMEN

NADPH oxidase enzymes (NOX) are involved in all stages of carcinogenesis, but their expression levels and prognostic value in breast cancer (BC) remain unclear. Thus, we aimed to assess the expression and prognostic value of NOX enzymes in BC samples using online databases. For this, mRNA expression from 290 normal breast tissue samples and 1904 BC samples obtained from studies on cBioPortal, Kaplan-Meier Plotter, and The Human Protein Atlas were analyzed. We found higher levels of NOX2, NOX4, and Dual oxidase 1 (DUOX1) in normal breast tissue. NOX1, NOX2, and NOX4 exhibited higher expression in BC, except for the basal subtype, where NOX4 expression was lower. DUOX1 mRNA levels were lower in all BC subtypes. NOX2, NOX4, and NOX5 mRNA levels increased with tumor progression stages, while NOX1 and DUOX1 expression decreased in more advanced stages. Moreover, patients with low expression of NOX1, NOX4, and DUOX1 had lower survival rates than those with high expression of these enzymes. In conclusion, our data suggest an overexpression of NOX enzymes in breast cancer, with certain isoforms showing a positive correlation with tumor progression.

Asunto(s)

Neoplasias de la Mama , NADPH Oxidasas , Humanos , Femenino , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Oxidasas Duales/genética , Neoplasias de la Mama/genética , Pronóstico , Especies Reactivas de Oxígeno/metabolismo , ARN Mensajero/genética , Expresión Génica , NADPH Oxidasa 4/genética , NADPH Oxidasa 1/genética

RESUMEN

Thyroid diseases are more prevalent in women, and this difference seems to be associated with the oxidative stress found in the thyroid of females. Thyroid NADPH Oxidase 4 (NOX4) was shown to respond to estrogen, which can also modulate TGF-ß1, a potent stimulator of NOX4. This study aimed to investigate the effects of TGF-ß1 on redox homeostasis parameters in the rat thyroid cell PCCL3 and the interrelationship between estrogen and TGF-ß1. TGF-ß1 treatment increased both intra- and extracellular ROS generation along with NOX4 expression and reduced GPX and catalase activities, extracellular H2O2 scavenging capacity, and reduced thiol content. TGF-ß1 mRNA and protein expression are higher in female thyroid glands of rats in comparison to males. Moreover, 17ß-estradiol treatment enhanced TGF-ß1 mRNA in PCCL3 cells, decreased extracellular bioavailability but did not activate Smad pathway. Our data suggest that higher levels of TGF-ß1 in females are potentially related to higher ROS availability which may be associated with the sex disparity in thyroid disorders.

Asunto(s)

Glándula Tiroides , Factor de Crecimiento Transformador beta1 , Animales , Estrógenos/metabolismo , Femenino , Peróxido de Hidrógeno/metabolismo , Masculino , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , NADPH Oxidasas/metabolismo , Oxidación-Reducción , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Caracteres Sexuales , Glándula Tiroides/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo

RESUMEN

PURPOSE: The tumor immune microenvironment (TIME) is now considered as an important factor during gastric cancer (GC) development. This study identified a novel immune-related risk model for predicting prognosis and assessing the immune status of GC patients. METHODS: Transcriptomic data were obtained from the TCGA database. The differential expressed immune-related genes (IRGs) were identified through the ImmPort portal. Enrichment analysis was performed to explore the potential molecular mechanism of these IRGs. By the Cox regression analysis, we constructed the immune prognostic model. Then, the association between the model and the immune microenvironment was estimated. The model was validated in the GSE84433 dataset. RESULTS: Totally, we identified 222 differentially expressed IRGs. These IRGs were closely correlated with immune response and immune signaling pathways. Through the Cox regression analysis, we developed the immune prognostic model based on the expression of seven IRGs (CXCL3, NOX4, PROC, FAM19A4, RNASE2, IGHD2-15, CGB5). Patients were stratified into two groups according to immune-related risk scores. Survival analysis indicated that the prognosis of high-risk patients was poorer than low-risk patients. Moreover, the immune-related risk score was an independent prognostic biomarker. More importantly, we found that the infiltration level of immunosuppressive cells and the expression of inhibitory immune checkpoints were higher in high-risk patients. The immune microenvironment tended to be a suppressive status in patients with high-risk scores. CONCLUSION: This study demonstrated that our model had predictive value for prognosis and the TIME in GC. It might be a robust tool to improve personalized patient management.

Asunto(s)

Inmunidad/genética , Modelos Inmunológicos , Neoplasias Gástricas/inmunología , Microambiente Tumoral/inmunología , Quimiocinas CXC/genética , Citocinas/genética , Bases de Datos Genéticas , Progresión de la Enfermedad , Enanismo Hipofisario/genética , Neurotoxina Derivada del Eosinófilo/genética , Expresión Génica/inmunología , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Tolerancia Inmunológica/genética , NADPH Oxidasa 4/genética , Células Madre Neoplásicas/inmunología , Pronóstico , Análisis de Regresión , Factores de Riesgo , Neoplasias Gástricas/mortalidad , Análisis de Supervivencia , Transcriptoma , Microambiente Tumoral/genética

RESUMEN

We addressed the involvement of the receptor for advanced glycation end products (RAGE) in the impairment of the cellular cholesterol efflux elicited by glycated albumin. Albumin was isolated from type 1 (DM1) and type 2 (DM2) diabetes mellitus (HbA1c > 9%) and non-DM subjects (C). Moreover, albumin was glycated in vitro (AGE-albumin). Macrophages from Ager null and wild-type (WT) mice, or THP-1 transfected with siRNA-AGER, were treated with C, DM1, DM2, non-glycated or AGE-albumin. The cholesterol efflux was reduced in WT cells exposed to DM1 or DM2 albumin as compared to C, and the intracellular lipid content was increased. These events were not observed in Ager null cells, in which the cholesterol efflux and lipid staining were, respectively, higher and lower when compared to WT cells. In WT, Ager, Nox4 and Nfkb1, mRNA increased and Scd1 and Abcg1 diminished after treatment with DM1 and DM2 albumin. In Ager null cells treated with DM-albumin, Nox4, Scd1 and Nfkb1 were reduced and Jak2 and Abcg1 increased. In AGER-silenced THP-1, NOX4 and SCD1 mRNA were reduced and JAK2 and ABCG1 were increased even after treatment with AGE or DM-albumin. RAGE mediates the deleterious effects of AGE-albumin in macrophage cholesterol efflux.

Asunto(s)

HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Adulto , Animales , Estudios de Casos y Controles , Línea Celular , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Hemoglobina Glucada/genética , Hemoglobina Glucada/metabolismo , Productos Finales de Glicación Avanzada/sangre , Productos Finales de Glicación Avanzada/farmacología , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Receptor para Productos Finales de Glicación Avanzada/deficiencia , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Albúmina Sérica Humana/metabolismo , Albúmina Sérica Humana/farmacología , Células THP-1 , Triglicéridos/sangre

RESUMEN

Asthma outcomes is aggravated in obese patients. Excess of methylglyoxal (MGO) in obese/diabetic patients has been associated with diverse detrimental effects on cell function. This study aimed to evaluate the effects of long-term oral intake of MGO on ovalbumin-induced eosinophil inflammation. Male C57/Bl6 mice received 0.5% MGO in the drinking water for 12 weeks. Mice were sensitized and challenged with ovalbumin (OVA), and at 48 h thereafter, bronchoalveolar lavage (BAL) fluid and lungs were collected for cell counting, morphological analysis, and ELISA, mRNA expressions and DHE assays. In MGO-treated mice, OVA challenge significantly increased the peribronchiolar infiltrations of inflammatory cells and eosinophils compared with control group. Higher levels of IL-4, IL-5, and eotaxin in BAL fluid were also detected in MGO compared with control group. In addition, lung tissue of MGO-treated mice displayed significant increases in mRNA expressions of NF-κB and iNOS whereas COX-2 expression remained unchanged. The high TNF-α mRNA expression observed in lungs of OVA-challenged control mice was not further increased by MGO treatment. In MGO group, OVA-challenge increased significantly the NOX-2 and NOX-4 mRNA expressions, without affecting the NOX-1 expression. Levels of reactive-oxygen species (ROS) were significantly higher in lungs of MGO-treated mice, and no further increase by OVA-challenge was observed. In conclusion, 12-week intake of MGO exacerbates Th2-mediated airway eosinophil infiltration by activation of NF-kB/iNOS-dependent signaling pathway and positive regulation of NOX-2 and NOX-4 in the lung tissues. Scavengers of MGO could be an option to prevent obesity-related asthma.

Asunto(s)

Asma/metabolismo , Eosinófilos/inmunología , Obesidad/metabolismo , Piruvaldehído/metabolismo , Células Th2/inmunología , Alérgenos/inmunología , Animales , Movimiento Celular , Modelos Animales de Enfermedad , Humanos , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , FN-kappa B/metabolismo , Ovalbúmina/inmunología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal

RESUMEN

Inflammation involves the activation of redox-sensitive transcription factors, e.g., nuclear factor κB (NF-κB). Administration of (-)-epicatechin to high-fructose-fed rats prevented NF-κB activation and up-regulation of the NADPH oxidase 4 (NOX4) in the kidney cortex. These results add mechanistic insights into the action of (-)-epicatechin diminishing inflammatory responses.

Asunto(s)

Catequina/metabolismo , Fructosa/metabolismo , Corteza Renal/enzimología , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 4/metabolismo , FN-kappa B/metabolismo , Animales , Corteza Renal/metabolismo , Masculino , NADPH Oxidasa 1/genética , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 4/genética , FN-kappa B/genética , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo

RESUMEN

BACKGROUND: Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD. METHODS: A total of 207 biopsy-proven NAFLD patients [simple steatosis (n = 27); nonalcoholic steatohepatitis (NASH) (n = 180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR. RESULTS: Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; P < 0.01) and triglycerides (TGL) (TT vs XA; P < 0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CA + AA genotypes was significant associated with alanine aminotransferase (ALT) (CA + AA vs CC; P = 0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, P < 0.01) and those who were more obese (32.2 vs 29.0 kg/m2, P < 0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH. CONCLUSIONS: There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients.

Asunto(s)

Síndrome Metabólico/genética , NADPH Oxidasa 4/genética , NADPH Oxidasas/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Brasil/epidemiología , Estudios Transversales , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Resistencia a la Insulina/genética , Cirrosis Hepática/sangre , Cirrosis Hepática/enzimología , Cirrosis Hepática/epidemiología , Cirrosis Hepática/genética , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/enzimología , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Fenotipo , Factores de Riesgo

RESUMEN

Na+ /I- symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d-5d) or 21 (R1d-21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time-dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d-5d, it was still high in R1d-21d. On the other hand, iodide uptake was rapidly down-regulated in R1d-21d, but not in R1d-5d, suggesting that the increased TPO activity in R1d-21d led to increased intraglandular organified iodine (I-X), which is known to inhibit iodide uptake. Since TGFß has been shown to mediate some effects of I-X, we evaluated TGFß and TGFß receptor mRNA levels, which were increased in R1d-21d. Moreover, it has been demonstrated that TGFß stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2 O2 generation in R1d-21d. Finally, we evaluated the effect of H2 O2 on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I-X, TGFß, NOX4 and increased ROS production.

Asunto(s)

Bocio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Simportadores/metabolismo , Glándula Tiroides/metabolismo , Animales , Transporte Biológico , Regulación de la Expresión Génica , Bocio/genética , Peróxido de Hidrógeno/metabolismo , Yoduros/metabolismo , NADPH Oxidasa 4/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta1/genética

RESUMEN

Metabolic syndrome (MetS) is a risk factor for sudden cardiac death in humans, but animal models are needed for the study of this association. Grape pomace (GP), obtained from the winemaking process, contains phenolic compounds with potential cardioprotective effects. The aim of this study was to evaluate if a high-fat-fructose (HFF) diet facilitates the occurrence of arrhythmias during the reperfusion, and if a GP supplementation could counteract these effects. Wistar rats were fed with control (Ctrl), HFF diet and HFF plus GP (1 g kg-1 day-1) for six weeks. The HFF diet induces characteristic features of MetS (higher systolic blood pressure, dyslipidemia and insulin resistance) which was attenuated by GP supplementation. In addition, HFF induced increased reperfusion arrhythmias that were reduced upon GP supplementation. GP also reduced the non-phosphorylated form of connexin-43 (Cx43) while enhancing heart p-AKT and p-eNOS protein levels and reducing Nox4 levels enhanced by the HFF diet, indicating that GP may increase NO bioavailability in the heart. We found a murine model of MetS with increased arrhythmogenesis and translational value. Furthermore, GP prevents diet-induced heart dysfunction and metabolic alterations. These results highlight the potential utilization of winemaking by-products containing significant amounts of bioactive compounds to prevent/attenuate MetS-associated cardiovascular pathologies.

Asunto(s)

Arritmias Cardíacas/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Fructosa/efectos adversos , Preparaciones de Plantas/metabolismo , Vitis/química , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Fructosa/metabolismo , Humanos , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Ratas Wistar

RESUMEN

This work investigated the capacity of (-)-epicatechin to prevent the renal damage induced by LPS administration in rats. Male Sprague Dawley rats were fed for 4 days a diet without or with supplementation with (-)-epicatechin (80mg/kg BW/d), and subsequently i.p. injected with lipopolysaccharide (LPS). Six hours after injection, LPS-treated rats exhibited increased plasma creatinine and urea levels as indicators of impaired renal function. The renal cortex of the LPS-treated rats showed: i) increased expression of inflammatory molecules (TNF-α, iNOS and IL-6); ii) activation of several steps of NF-κB pathway; iii) overexpression of TLR4, and iv) higher superoxide anion production and lipid peroxidation index in association with increased levels of gp91phox and p47phox (NOX2) and NOX4. Pretreatment with dietary (-)-epicatechin prevented the adverse effects of LPS challenge essentially by inhibiting TLR4 upregulation and NOX activation and the consequent downstream events, e.g. NF-kB activation.

Asunto(s)

Antiinflamatorios/farmacología , Antioxidantes/farmacología , Catequina/farmacología , Riñón/efectos de los fármacos , Nefritis/prevención & control , Administración Oral , Animales , Creatinina/sangre , Regulación de la Expresión Génica , Inyecciones Intraperitoneales , Interleucina-6/genética , Interleucina-6/inmunología , Riñón/inmunología , Riñón/patología , Lipopolisacáridos , Masculino , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/inmunología , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/inmunología , NADPH Oxidasas/genética , NADPH Oxidasas/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Nefritis/inducido químicamente , Nefritis/genética , Nefritis/patología , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/inmunología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Urea/sangre

RESUMEN

BACKGROUND: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene. METHODS AND RESULTS: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele. CONCLUSIONS: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.

Asunto(s)

Caveolina 1/genética , Glucosa/metabolismo , Resistencia a la Insulina/genética , Metabolismo de los Lípidos/genética , Tejido Adiposo/metabolismo , Adolescente , Adulto , Anciano , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Aldosterona/metabolismo , Animales , Glucemia/efectos de los fármacos , Colesterol/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Eplerenona , Femenino , Frecuencia de los Genes , Homeostasis , Humanos , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/farmacología , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Receptores de Mineralocorticoides/metabolismo , Resistina/genética , Resistina/metabolismo , Proteínas Plasmáticas de Unión al Retinol/genética , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Espironolactona/análogos & derivados , Espironolactona/farmacología , Triglicéridos/metabolismo , Adulto Joven