Felipe J. Chaves

Microalbuminuria and oxidative stress in essential hypertension

Objective.u2002 To assess the relationship between microalbuminuria and oxidative stress in mononuclear peripherals cells in essential hypertension.

A novel CYBA variant, the -675A/T polymorphism, is associated with essential hypertension.

Objective Oxidative stress is implicated in hypertension and the NADPH oxidase systems constitute the main source of superoxide in vascular wall. We searched for new polymorphisms within the CYBA promoter, the human gene that encodes the p22phox protein, and studied their potential association with essential hypertension. Design A case–control study in a random sample of the general population. Methods CYBA polymorphisms were determined by restriction fragment length polymorphism and allelic discrimination. NADPH oxidase activity was quantified in phagocytic cells by chemiluminescence. Results We identified three novel polymorphisms, at positions –852, –675 and –536 from the ATG codon. Only the –675A/T polymorphism associated with essential hypertension. The prevalence of the TT genotype and the T allele frequency were significantly higher (P < 0.05) in hypertensives than in normotensives. Furthermore, TT hypertensives exhibited higher (P < 0.05) systolic blood pressure values than TA/AA hypertensives. Increased phagocytic NADPH oxidase activity was observed in TT subjects compared to TA and AA individuals (P < 0.05). Enhanced carotid intima–media thickness, a surrogate marker of atherosclerosis, was found in TT subjects compared to TA and AA individuals (P < 0.05). Finally, mutagenesis experiments demonstrated a functional role of this polymorphism on the CYBA promoter activity. Conclusion The –675A/T CYBA polymorphism may be a novel genetic marker associated with essential hypertension. Furthermore, TT subjects exhibit features of NADPH oxidase-mediated oxidative stress and asymptomatic atherosclerosis.

Urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), a reliable oxidative stress marker in hypertension

The potential use of oxidative stress products as disease markers and progression is an important aspect of biomedical research. In the present study, the quantification of urine 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) concentration has been used to express the oxidation status of hypertensive subjects. 8-oxo-dG has been simultaneously isolated and assayed in nuclear (nDNA) and mitochondrial DNA (mtDNA). In addition, oxidative stress of mononuclear cells has been estimated by means of GSH and GSSG levels and GSSG/GSH ratio in hypertensive subjects before and after antihypertensive treatment. It is shown that oxidative stress decreases significantly in hypertensive patients after treatment the effect being accompanied by reduction of their blood pressure. A significant correlation is observed comparing the yield of urine 8-oxo-dG and that isolated from mitochondria DNA. Moreover, urinary excretion of 8-oxo-dG also correlates with the GSSG/GSH ratio of cells. Conclusion: urine 8-oxo-dG assay is a good marker for monitoring oxidative stress changes in hypertensives.

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia.

BACKGROUND AND AIMSnXanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR).nnnMETHOD AND RESULTSn40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity.nnnCONCLUSIONSnSubjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.

Association of a Mineralocorticoid Receptor Gene Polymorphism With Hypertension in a Spanish Population

BACKGROUNDnTo assess the association of polymorphisms and haplotypes of the mineralocorticoid receptor (MR) (NR3C2) gene to the risk of essential hypertension (HTN) in a Spanish population.nnnMETHODSnThis is a population-based study which included 1,502 subjects (748 women) >18 years old. Twenty-four polymorphisms of NR3C2 gene were analyzed by using SNPlex (Genotyping System based on OLA/PCR technology).nnnRESULTSnAlleles of the single-nucleotide polymorphism (SNP) rs5522 were significantly associated with the risk of HTN, both in the recessive and codominant models adjusted by age, gender, and body mass index (BMI). Genotype GG of the rs5522 showed to be protective against HTN odds ratio (OR) 0.10 (0.02-0.56), P < 0.01. One haplotype, which included the G allele of the rs5522, was also associated with reduced risk of HTN and four haplotypes which included the A allele were associated with increased risk of HTN. When the 24-h urinary sodium excretion and the estimated glomerular filtration rate (eGFR) were added, they did not reduce the significance level. Interaction between genotypes of the rs5522 and quartiles of 24-h sodium excretion has been observed. In subjects with the AA genotype, those with higher urinary sodium excretion had the lowest risk to be hypertensive.nnnCONCLUSIONnA functional polymorphism of the NR3C2 gene was associated with risk of HTN. The data provided in this study seems to give credit to the hypothesis of the participation of MR gene in the development of HTN, although further studies are necessary to better assess its real impact.

Xanthine oxidoreductase polymorphisms: influence in blood pressure and oxidative stress levels.

Objectives Oxidative stress can modulate blood pressure levels in different models. Xanthine oxidoreductase is one of the enzymes producing free radicals in the cardiovascular system, and it can contribute to the increment of the oxidative stress and, consequently, blood pressure. We analyzed the association between the −337GA and 565+64CT polymorphisms of the xanthine oxidoreductase gene with blood pressure and oxidative stress levels. Methods These polymorphisms were studied in a case–control study (185 patients with hypertension and 385 normotensive controls), we found that these polymorphisms were related to blood pressure levels. This association was high in patients with hypertension and showed an additive effect but did not increase the risk of developing hypertension. We studied an additional and independent sample of patients with hypertension (n=100) to know the association of these polymorphisms with oxidative stress levels. Results We found that these polymorphisms were related to blood pressure levels. This association was high in hypertensive patients and showed an additive effect, but does not increase the risk of developing hypertension. We have found that the same alleles related with higher blood pressure−337A and 565+64C were related with increased oxidative stress in patients with hypertension. Conclusions Our results suggest that polymorphisms −337GA and 565+64CT of xanthine oxidoreductase gene are related with blood pressure and oxidative stress in hypertension, adding evidence to the role of xanthine oxidoreductase and oxidative stress in blood pressure.

Polimorfismos genéticos del sistema renina- angiotensina e hipertensión arterial esencial en la población española

Fundamento Analizar la asociacion entre los principales polimorfismos geneticos descritos en el sistema renina-angiotensina y la hipertension arterial (hta) esencial en una muestra de poblacion espanola. Pacientes y metodo Estudio de casos y controles con 185 hipertensos esenciales (edad [de] 39,6 [7,5] anos, 52% mujeres, presion arterial sistolica [pas] de 151,2 [17,4] mmhg, presion arterial diastolica [pad] de 96,0 [9,4] mmhg) y 350 controles normotensos apareados por edad y sexo de una muestra de poblacion general de la Comunidad Valenciana (edad 39,4 [8,0] anos, 51,7% mujeres, PAS de 116,0 [12,0] mmhg, pad de 69,6 [8,5] mmhg). Se realizo pcr para la determinacion de los polimorfismos i/d del gen de la enzima conversiva de la angiotensina (eca), a-6g y m235t del gen del angiotensinogeno y a1166c del gen del receptor at1 de la angiotensina ii. Resultados No hubo diferencias en las distribuciones genotipicas ni alelicas entre casos y controles. En hipertensos tampoco hubo diferencias al comparar genotipos y distribucion alelica segun terciles de valores de presion arterial o presencia/ausencia de antecedentes familiares de hta. Solo en mujeres se detecto un mayor riesgo de hipertension en las pacientes con haplotipos que contenian el alelo c del polimorfismo a1166c con los alelos a del polimorfismo a-6g(p = 0,007) o t del polimorfismo m235t (p = 0,007). Conclusiones No se hallo relacion entre la hta esencial y los polimorfismos i/d del gen de la eca, m235t y a-6g del gen del angiotensinogeno, ni a1166c del gen del receptor at1. En la poblacion de mujeres jovenes se observa un efecto epistatico entre polimorfismos del receptor at1 y del angiotensinogeno.

One-year follow-up of clinical, metabolic and oxidative stress profile of morbid obese patients after laparoscopic sleeve gastrectomy. 8-oxo-dG as a clinical marker

Obesity has grown worldwide over the last few decades. In its different degrees, obesity is accompanied by many clinical and biochemical alterations reflecting the pathological condition of various body tissues. Among the mechanisms underlying the pathogenesis of obesity and associated complications, oxidative stress (OS) may be playing an important role. In the present study, we have characterized at systemic level the degree of OS status in a group of morbid obese patients (BMI>40 kg/m2) at basal sate and its modulation during one year after bariatric surgery using the laparoscopic sleeve gastrectomy (LSG) technique. As compared with normal weight subjects matched in age, peripheral blood mononuclear cells (PBMc) of obese patients present a significant reduction of the antioxidant enzyme activities superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) as well as a significant increase of the oxidized/reduced glutathione ratio (GSSG/GSH) in these cells. Lipid peroxidation is significantly increased in the patient group as shown by the increased levels of malondialdehyde (MDA) in PBMc and the amount of F2-Isoprostanes (F2-IsoPs) released in urine. In addition, the DNA damage product 8-oxo-7,8-2′-deoxyguanosine (8-oxo-dG) was also observed to be increased in serum and urine of morbid obese patients as compared with the control group. After LSG, an improvement of their ponderal and metabolic profile was accompanied by a progressive recovery of antioxidant enzyme activities and the decline of oxidative byproducts both in PBMc and biological fluids. The observed changes of urinary 8-oxo-dG levels correlate positively with its serum concentration, the lipid peroxidation products MDA and F2-IsoPs, triglycerides, glucose, insulin, HOMA index and body weight and negatively with the percentage of weight and BMI loss and antioxidant activities. We conclude that the analysis of urinary 8-oxo-dG could be validated as a useful marker for the monitoring of ponderal and metabolic status of morbid obese patients.

Inefficient arterial hypertension control in patients with metabolic syndrome and its link to renin-angiotensin-aldosterone system polymorphisms

There is evidence that uncontrolled arterial hypertension (AHT) in patients with metabolic syndrome (MS) increases cardiovascular risks. The renin–angiotensin–aldosterone system (RAAS) and its polymorphisms apparently confer a genetic risk for uncontrolled AHT. This study aims to investigate the influence of RAAS polymorphisms on AHT control in patients diagnosed with MS. This is a two-stage population-based nested case–control pilot study (n=1514). We differentiated between MS-diagnosed patients and non-MS patients (ATP-III criteria) and selected those individuals diagnosed with AHT from each group (n=161 and n=156, respectively). Those who successfully controlled their AHT (controls) and those who did not were compared. In the MS population, the C/G and G/G genotypes of single-nucleotide polymorphism rs1040288 (NR3C2) and A/G and G/G of rs11099680 (NR3C2) were associated with uncontrolled AHT (odds ratio (OR)=2.94 (1.34–6.47) and OR=2.54 (1.09–5.93), respectively). According to Akaikes information criteria, the best adjusted model included gender and age as confounding variables (adjusted OR (ORa)=2.91 (1.31–6.46) and ORa=2.67 (1.13–6.31), respectively). Regarding rs1040288, an ORa of 4.03 (1.44–11.26) was obtained for the saturated model (adjusted for gender, age, waist-to-hip ratio, body mass index, biochemical profile, renal damage, smoking habit and anti-AHT treatment). Yet, when the same analysis was performed on the non-MS population, no association was found between rs11099680 and the failure to control AHT. The results reveal a possible association between the rs11099680 RAAS polymorphism and uncontrolled AHT in MS-diagnosed patients. rs1040288 appears to be associated with uncontrolled blood pressure regardless of MS profile.

Determinantes de la lipemia posprandial medida como perfil diurno de triglicéridos en personas no diabéticas con normolipemia

Fundamento y objetivo Conocer los determinantes clinicos y biologicos de la lipemia posprandial, medida con la autodeterminacion diurna de trigliceridos en sangre capilar (TGc), en personas sin dislipemia ni diabetes. Pacientes y metodo Hemos estudiado a 76 personas sanas (45 mujeres premenopausicas) con normolipemia y sin diabetes. La determinacion de los TGc se realizo mediante Accutrend ® durante 3 dias en 6 puntos establecidos: ayunas, inmediatamente antes y 3 h despues de comer y de cenar, y antes de acostarse. Se midio el area bajo la curva de TGc (ABC-TGc) como expression de la lipemia posprandial diurna. Resultados El ABC-TGc fue significativamente mayor en los varones (26,20 [11,00]) que en las mujeres (19,12 [6,57]) (pxa0 Conclusiones Los determinantes independientes de la lipemia posprandial en nuestra poblacion son el perimetro de la cintura y el HOMA.BACKGROUND AND OBJECTIVEnWe decided to evaluate the clinical and biochemical predictors of postprandial lipemia, measured as daylong capillarly triglycerides (TGc) profiles, in normolipidemic non diabetic subjects.nnnPATIENTS AND METHODnWe studied 76 normolipidemic non diabetic subjects (45 premenopausal females). Accutrend was used to measure daylong TGc profiles during 3 days in 6 previously standardized points: fasting, pre and 3 h after dinner and lunch and at bedtime. The area under the curve of TGc (AUC-TGc) was determined as expression of postprandial lipemia.nnnRESULTSnMales showed significantly higher AUC-TGc (26.20 [11.00] vs 19.12 [6.57] in females; p < 0.001). Obese showed significantly higher values of AUC-TGc (27.87 [12.47] vs 20.05 [7.04]; p < 0.01). The AUC-TGc correlated with: age (r = 0.242; p < 0.05), body mass index (r = 0.312; p < 0.01), waist circumference (r = 0.394; p < 0.01), fasting plasma triglyceride (r = 0.634; p < 0.001), fasting insulinemia (r = 0.485; p < 0.001) and fasting HOMA (r = 0.484; p < 0.001). The multivariate analysis showed that HOMA (regression coefficient: 0.352; p = 0.02) and waist circumference (regression coefficient: 0.4; p = 0.05) were independent predictors of the AUC-TGc.nnnCONCLUSIONSnIndependent determinants of postprandial lipemia were waist circumference and HOMA.