Associação entre Nível de Big Endotelina-1 Plasmática e a Gravidade da Doença Arterial Coronariana em Pacientes com Infarto do Miocárdio sem Supradesnivelamento do Segmento ST / Association between Plasma Big Endothelin-1 Level and The Severity of Coronary Artery Disease in Patients with Non-ST Segment-Elevated Myocardial Infarction

Resumo Fundamento A estratificação de risco precoce com biomarcadores simples é essencial em pacientes com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST). Objetivo Este estudo tem o objetivo de avaliar a associação entre nível de big endotelina-1 plasmática (ET-1) e o escore SYNTAX (SS) em pacientes com IAMSSST. Métodos Foram recrutados 766 pacientes com IAMSSST que passaram por angiografia coronária. Os pacientes foram divididos em três grupos: SS baixo (≤22), SS intermediário (23-32), e SS alto (>32). A correlação de Spearman, o ajuste de curva suave, a regressão logística, e a análise de curva característica de operação do receptor (ROC) foram realizados para avaliar a associação entre o nível de big ET-1 plasmática e o SS. Um p-valor <0.05 foi considerado estatisticamente significativo. Resultados Foi identificada uma correlação significativa entre a big ET-1 e o SS (r=0,378, p<0,001). A curva suavizada indicou uma correlação positiva entre o nível de big ET-1 plasmática e o SS. A análise de curva ROC demonstrou que a área sob a curva foi de 0,695 (0,661-0,727) e o ponto de corte ideal do nível de big ET-1 plasmática foi de 0,35 pmol/l. A regressão logística demonstrou que a big ET-1 elevada era um preditor independente de SS intermediário a alto em pacientes com IAMSSST, seja como variável contínua [RC (IC 95%: 1,110 (1,053-1,170), p<0,001] ou como variável categórica [RC (IC 95%: 2,962 (2,073-4,233), p<0,001]. Conclusão Em pacientes com IAMSSST, o nível de big ET-1 plasmática estava significativamente correlacionado ao SS. O nível de big ET-1 plasmática elevado foi um preditor independente para SS intermediário a alto.

Abstract Background Early risk stratification with simple biomarkers is essential in patients with non-ST segment-elevation myocardial infarction (NSTEMI). Objective This study aimed to evaluate the association between plasma big endothelin-1 (ET-1) level and the SYNTAX score (SS) in patients with NSTEMI. Methods A total of 766 patients with NSTEMI undergoing coronary angiography were recruited. Patients were divided into three groups: low SS (≤22), intermediate SS (23-32), and high SS (>32). Spearman correlation, smooth curve fitting, logistic regression, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the association between plasma big ET-1 level and the SS. A p-value <0.05 was considered statistically significant. Results There was a significant correlation between the big ET-1 and the SS (r=0.378, p<0.001). The smoothing curve indicated a positive correlation between the plasma big ET-1 level and the SS. The ROC curve analysis showed that the area under the curve was 0.695 (0.661-0.727) and the optimal cutoff of plasma big ET-1 level was 0.35pmol/l. Logistic regression showed that elevated big ET-1 was an independent predictor of intermediate-high SS in patients with NSTEMI, whether entered as a continuous variable [OR (95% CI): 1.110 (1.053-1.170), p<0.001] or as a categorical variable [OR (95% CI): 2.962 (2.073-4.233), p<0.001]. Conclusion In patients with NSTEMI, the plasma big ET-1 level was significantly correlated with the SS. Elevated plasma big ET-1 level was an independent predictor for intermediate-high SS.

Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemia / Efeito antioxidante de antagonista dos receptores de endotelina-1 protege ratos contra lesão renal crônica induzida por hipertensão e hiperglicemia

ABSTRACT Hypertension and Diabetes mellitus are the two main causes of chronic kidney disease that culminate in the final stage of kidney disease. Since these two risk factors are common and can overlap, new approaches to prevent or treat them are needed. Macitentan (MAC) is a new non-selective antagonist of the endothelin-1 (ET-1) receptor. This study aimed to evaluate the effect of chronic blockade of ET-1 receptor with MAC on the alteration of renal function observed in hypertensive and hyperglycemic animals. Genetically hypertensive rats were divided into control hypertensive (HT-CTL) group, hypertensive and hyperglycemic (HT+DIAB) group, and hypertensive and hyperglycemic group that received 25 mg/kg macitentan (HT-DIAB+MAC25) via gavage for 60 days. Kidney function and parameters associated with oxidative and nitrosative stress were evaluated. Immunohistochemistry for neutrophil gelatinase-associated lipocalin (NGAL), ET-1, and catalase in the renal cortex was performed. The HT+DIAB group showed a decrease in kidney function and an increase in NGAL expression in the renal cortex, as well as an increase in oxidative stress. MAC treatment was associated with attenuated ET-1 and NGAL production and increases in antioxidant defense (catalase expression) and nitric oxide production. In addition, MAC prevented an increase in oxidant injury (as measured by urinary hydroperoxide and lipid peroxidation), thus improving renal function. Our results suggest that the antioxidant effect of the ET-1 receptor antagonist MAC is involved in the improvement of kidney function observed in hypertensive and hyperglycemic rats.

RESUMO Hipertensão e Diabetes Mellitus figuram como as duas principais causas de doença renal crônica que culmina em doença renal terminal. Uma vez que os dois fatores de risco são comuns e podem se sobrepor, novas abordagens preventivas e terapêuticas se fazem necessárias. O macitentan (MAC) é um novo antagonista não-seletivo dos receptores da endotelina-1 (ET-1). O presente estudo teve como objetivo avaliar os efeitos do bloqueio crônico dos receptores da ET-1 com MAC sobre a alteração da função renal em animais hipertensos e hiperglicêmicos. Ratos geneticamente hipertensos foram divididos em grupos com animais hipertensos de controle (HT-CTL), hipertensos e hiperglicêmicos (HT+DIAB) e hipertensos e hiperglicêmicos tratados com 25 mg/kg de macitentan (HT-DIAB+MAC25) via gavagem por 60 dias. Foram avaliados função renal e parâmetros associados ao estresse oxidativo e nitrosativo. Exames de imunoistoquímica foram realizados para lipocalina associada à gelatinase neutrofílica (NGAL), ET-1 e catalase no córtex renal. O grupo HT+DIAB exibiu diminuição da função renal e aumento na expressão de NGAL no córtex renal, bem como estresse oxidativo aumentado. O tratamento com MAC foi associado a atenuação da produção de ET-1 e NGAL e maior ativação das defesas antioxidantes (expressão de catalase) e elevação da produção de óxido nítrico. Além disso, o MAC evitou exacerbação da lesão oxidante (medida por hidroperóxidos urinários e peroxidação lipídica), melhorando assim a função renal. Nossos resultados sugerem que o efeito antioxidante do antagonista dos receptores da ET-1 MAC esteja imbricado no aprimoramento da função renal observada em ratos hipertensos e hiperglicêmicos.

Endotelina-1, proteína C reactiva ultrasensible y actividad antioxidante en pacientes con hipotiroidismo subclínico y en eutiroideos con autoinmunidad tiroidea. Efectos del tratamiento con levotiroxina / Endothelin-1, high sensitivity C reactive protein and antioxidant activity in subclinical hypothyroid patients. Effects of levothyroxine treatment

RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".

ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.

Evaluation of smoking as an additional risk factor for cardiovascular diseases among hemodialysis patients by increased levels of II-6, TNFα, hs-CRP and Endothelin-1 / Evaluación del tabaquismo como factor de riesgo adicional de enfermedades cardiovasculares en pacientes en hemodiálisis según niveles elevados de II-6, TNFα, hs-CRP y Endotelina-1

INTRODUCTION: Cardiovascular diseases (CVD) are one of the most common causes of mortality in chronic kidney disease. Smoking is a well defined risk factor for atherosclerotic cardiovascular disease. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), high sensitive C-reactive protein (hsCRP) and endothelin-1 (Et-1) have found elevated in chronic inflammatory process. OBJECTIVE: We aimed to evaluate if IL-6, TNF-alpha, hsCRP and ET-1 are increased in smoker hemodialysis (HD) patient compared to non-smoker HD individuals to potentially refer us cardiovascular diseases noninvasively. MATERIAL AND METHODS: 80 smoker and 50 non-smoker maintenance hemodialysis male patients with similar demographic characters, dialysis and support treatment and metabolic profile. In addition to routine tests, we took samples for evaluating IL-6, TNF-α, hsCRP and endothelin-1. P values were In smoker HD patients, IL-6, TNF-alpha, hsCRP and endothelin-1 levels were found increased level statistically significant compared to non-smoker indiviuals. CONCLUSION: This study may refer us that smoking is an additional risk factor among HD individuals by increased levels of IL-6, TNF-α, hsCRP and Et-1

INTRODUCCIÓN: Las enfermedades cardiovasculares (EC) constituyen una de las causas más frecuentes de mortalidad en los casos de enfermedad renal crónica. El tabaquismo es un factor de riesgo bien definido para la enfermedad cardiovascular aterosclerótica. Se encontraron valores elevados de Interleucina-6 (IL-6), factor de necrosis tumoral alfa (TNFα), proteína C-reactiva de alta sensibilidad (hs-CRP) y Endotelina-1 (Et-1) en el proceso inflamatorio crónico. OBJETIVO: El objetivo fue analizar si los valores de IL-6, TNFα, hs CRP y Et-1 son más elevados en los pacientes fumadores en hemodiálisis que en los no fumadores para predecir una posible enfermedad cardiovascular de forma no invasiva. MATERIAL Y MÉTODOS: Se incluyeron pacientes masculinos en hemodiálisis de mantenimiento, 80 fumadores y 50 no fumadores, similares en cuanto a sus características demográficas, tratamiento de diálisis y de mantenimiento, y perfil metabólico. Además de los análisis de rutina, se tomaron muestras para evaluar los valores de IL-6, TNFα, hs CRP y Endotelina-1. Se midieron los valores de p. RESULTADOS: Se halló una diferencia estadísticamente significativa en los niveles de IL-6, TNFα, hs CRP y Endotelina-1: fueron más elevados en los pacientes sometidos a hemodiálisis que eran fumadores en comparación con los no fumadores.CONCLUSIÓN: Este estudio podría demostrar que el tabaquismo es un factor de riesgo adicional para los pacientes que se tratan con hemodiálisis según muestran los valores elevados de IL-6, TNFα, hs CRP y Et-1

Expression of endothelin-1 and Ki-67 in normotensive and severe preeclamptic placentas / Expresión de endotelina-1 y Ki-67 en placentas normotensas y preeclampsia severa

SUMMARY: Severe preeclampsia (HELLP syndrome) is a life-threatening pregnancy complication, usually a severe form of preeclampsia. In this study, we aimed to examine histopathologic changes and Endothelin-1 and KI-67 expression levels by immunohistochemical methods in severe preeclamptic placentas. Severe preeclampsia and obstetric characteristics and biochemical and hematological characteristics of healthy subjects were compared. Placenta sections were stained with hematoxylin-eosin for histopathological examination. In the histopathological examination of severe preeclamptic placenta, degeneration in synaptic and cytotrophoblastic cells, increase in insidious knots, fibrinoid necrosis, degeneration in endothelial cells, calcification and hyaline villous stains were observed. In the severe preeclampsia group, Ki-67 expression increased in decidua cells and inflammatory cells, while endothelial cells in the vessel wall and inflammatory cells in the villus and intervillous spaces increased. It is thought that angiogenetic and cellular proliferation is induced in a co-ordinated manner and significantly influences fetal development.

RESUMEN: La preeclampsia severa (síndrome de HELLP) es una complicación del embarazo potencialmente mortal, generalmente una forma grave de preeclampsia. En este estudio, nuestro objetivo fue examinar los cambios histopatológicos y los niveles de expresión de Endotelina-1 y Ki-67 mediante métodos inmunohistoquímicos en placentas preeclámpsicas graves. Se compararon la preeclampsia grave y las características obstétricas, además de las características bioquímicas y hematológicas de pacientes sanas. Las secciones de placenta se tiñeron con hematoxilina-eosina para examen histopatológico. En el examen histopatológico de placenta preeclampsia severa, se observó la degeneración en células sinápticas y citotrofoblásticas, un aumento de nudos insidiosos, necrosis fibrinoide, degeneración en las células endoteliales,calcificación y manchas vellosas hialinas. En el grupo de preeclampsia grave, la expresión de Ki-67 aumentó en células deciduas y células inflamatorias, mientras que las células endoteliales en la pared del vaso, y las células inflamatorias en las vellosidades y los espacios intervellosos aumentaron. Se cree que la proliferación angiogenética y celular se induce de forma coordinada y que influye significativamente en el desarrollo fetal.

Endothelin-1 expression in pulmonary hypertensive chickens by hypoxia / Expresión de Endotelina-1 en pollos con hipertensión arterial pulmonar por hipoxia hipobárica

ABSTRACT Objective. To determine the effect of hypobaric hypoxia exposition in pulmonary arterioles expression of endothelin-1 (ET-1). Materials and methods. Two groups of commercial broiler chickens were used: one of them were raised at 2638 (hypobaric hypoxia) and the other one at 300 m (relative normoxia) above sea level. Incidence of pulmonary hypertension (PH) was evaluated by calculating the cardiac mass index values and ET-1 protein expression was established in pulmonary arterioles by immunohistochemistry and morphometry. Results . ET-1 expression was higher in arterioles of animals exposed to hypoxia as compared to the low altitude exposed broilers (p<0.01). Arterioles from pulmonary hypertensive chickens (PHC) showed ET-1 higher expression than arterioles from healthy chickens (non-hypertensive, NHC) at low altitude, those exposed to hypobaric hypoxia (p<0.01). 53% of chickens subjected to altitude conditions developed pulmonary hypertension. Under normoxia, no chickens developed that pathology. Conclusions. Quantitative characteristics and sites of ET-1 expression in the lungs are important in the understanding of PH pathogenesis in broilers and the adapting mechanisms to hypobaric hypoxia, as to design new pharmacological approaches. This is a first approach which accounts for the abovementioned features in broilers subjected to natural conditions of normoxia and hypobaric hypoxia.

RESUMEN Objetivo. Determinar el efecto de la exposición a hipoxia hipobárica sobre la expresión de Endotelina-1 en arteriolash pulmonares. Material y métodos. Se utilizaron 2 grupos de pollos de engorde de una estirpe comercial: uno de ellos criados a 2638 y el otro, a 300 m de altitud. La incidencia de HAP se evaluó según los valores del índice de masa cardiaca y se compararon los niveles de expresión de la proteína ET-1 en arteriolas pulmonares de pollos de engorde sanos y enfermos por HAP mediante inmunohistoquímica y morfometría. Resultados. La expresión de la proteína ET-1 fue mayor en las arteriolas de los pollos expuestos a hipoxia hipobárica que en los criados bajo condiciones de normoxia relativa (p<0.01). Los animales enfermos por HAP presentaron mayor expresión de la proteína ET-1 en las arteriolas pulmonares que los animales sanos ubicados en las dos altitudes (p<0.01). 53% de los animales desarrollaron hipertensión pulmonar y ninguno de los mantenidos en normoxia lo hicieron. Conclusiones. El conocimiento de las características cuantitativas y lo sitios de expresión de la ET-1 son elementos importantes para entender aún más la patogenia de la HAP y el diseño de fármacos para su control. Este estudio constituye la primera aproximación cuantitativa relacionada con la expresión de ET-1 en pollos de engorde con HAP de origen hipóxico no inducida.

Analysis of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis / Análise da expressão imunohistoquímica e de western blotting da endotelina 1 e seus receptores na estenose mitral

Abstract Introduction: Rheumatic Fever represents a serious public health problem in developing countries, with thousands of new cases each year. It is an autoimmune disease, which occurs in response to infection by streptococcus A. Objective: The aim of this study was to evaluate the immunolabeling and protein expression for endothelin-1 and 3 (ET-1, ET-3) and its receptors (ETA, ETB) in rheumatic mitral valves. Methods: Immunohistochemistry was used to identify ET-1/ET-3 and ETA/ETB receptors in rheumatic and control mitral valves. Quantitative analysis of immunostaining for ET-1/ET-3 and ETA/ETB receptors was performed. In addition, western blot analysis was carried out to assess protein levels in tissue samples. Results: ET-1 and ETA receptor immunostaining predominated in stenotic valves, mainly associated with fibrotic regions, inflammatory areas and neovascularization. Quantitative analysis showed that the average area with positive expression of ET-1 was 18.21±14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06±13.13% and 9.20±11.09%. ET-3 did not have a significant expression. The correlation between the expression of both endothelin receptors were strongly positive (R=0.74, P=0.02), but the correlation between ET-1 and its receptor were negative for both ETA (R=-0.37, P=0.25), and ETB (R=-0.14, P=0.39). This data was supported by western blot analysis. Conclusion: The strong correlation between ET-1 and its receptors suggests that both play a role in the pathophysiology of rheumatic mitral valve stenosis and may potentially act as biomarkers of this disease. .

Resumo Introdução: A febre reumática representa um sério problema de saúde pública em países em desenvolvimento, com milhares de novos casos a cada ano. Ela é uma doença autoimune que ocorre em resposta à infecção por estreptococos do grupo A. Objetivo: O objetivo deste estudo foi avaliar a expressão proteica e imunohistoquímica para a endotelina-1 e 3 (ET-1 e ET-3) e seus receptores (ETA e ETB) em valvas mitrais reumáticas. Métodos: Imunohistoquímica foi utilizada para identificar receptores de ET1/ET3 e ETA/ETB em valvas mitrais reumáticas e controles. A análise quantitativa da expressão imunohistoquímica para receptores de ET1/ET3 e ETA/ETB foi também efetuada. Adicionalmente, foi feita análise do western blot para mensurar níveis de proteínas em extratos tissulares. Resultados: A expressão imunohistoquímica de ET-1 e de seu receptor predominou em valvas estenóticas, estando associada com regiões fibróticas, áreas inflamatórias e neovascularização. A análise quantitativa mostrou que a área média com expressão positiva para ET-1 foi de 18,21±14,96%. Para o ETA e o ETB, as áreas médias expressas foram, respectivamente, 15,06±13,13% e 9,20±11,09%. ET-3 não teve uma expressão significante. A correlação entre a expressão dos dois receptores de endotelina foi fortemente positiva (R=0,74, P=0,02); mas a correlação entre ET-1 e o seu receptor foi negativa tanto para ETA (R=-0,37, P=0,25) como para ETB (R=-0,14, P=0,39). Estes dados foram confirmados pela análise do western blot. Conclusão: A forte correlação entre ET-1 e seus receptores sugere que ambos têm papel importante na fisiopatologia da estenose mitral reumática, podendo potencialmente atuar como biomarcadores desta doença. .

Resveratrol plays important role in protective mechanisms in renal disease - mini-review / Resveratrol desempenha importante papel no mecanismo de proteção na doença renal - mini-revisão

Resveratrol (RESV) is a polyphenolic compound found in various plants, including grapes, berries and peanuts, and its processed foods as red wine. RESV possesses a variety of bioactivities, including antioxidant, anti-inflammatory, cardioprotective, antidiabetic, anticancer, chemopreventive, neuroprotective, renal lipotoxicity preventative, and renal protective effects. Numerous studies have demonstrated that polyphenols promote cardiovascular health. Furthermore, RESV can ameliorate several types of renal injury in animal models, including diabetic nephropathy, hyperuricemic, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and endothelial dysfunction. In addition, RESV can prevent the increase in vasoconstrictors, such as angiotensin II (AII) and endothelin-1 (ET-1), as well as intracellular calcium, in mesangial cells. Together, these findings suggest a potential role for RESV as a supplemental therapy for the prevention of renal injury.

Resveratrol (RESV) é um composto fenólico encontrado em várias plantas, como a uva e amendoim, e seus produtos derivados, como o vinho tinto. RESV possui uma variedade de bioatividades, incluindo antioxidantes, anti-inflamatória, cardioprotetoras, antidiabetes, anticancerígeno, quimiopreventivo, neuroprotetor, lipotoxicidade renal, e efeitos protetores renais. Numerosos estudos demonstraram que os polifenois promovem a saúde cardiovascular e podem reparar vários tipos de lesões renais em modelos animais, incluindo a nefropatia diabética, hiperuricemia, lesão induzida por droga, lesão induzida pela aldosterona, lesão de isquemia-reperfusão, lesões relacionadas com sepsis, e disfunção endotelial. Além disso, RESV pode prevenir o aumento de vasoconstritores, tais como angiotensina II (AII) e endotelina-1 (ET-1), bem como o cálcio intracelular, em células mesangiais. Em conjunto, estes resultados sugerem um importante papel para o RESV como uma terapia complementar na prevenção de lesões renais.

Relevancia de la hiperglucemia para la evolución y el desenlace de la hemorragia subaracnoidea aneurismática: evidencias y mecanismos / Relevance of hyperglycemia on the course and outcome of aneurysmal subarachnoid hemorrhage: evidence and mechanisms

La hemorragia subaracnoidea aneurismática (HSAa) puede tener un desenlace mortal en unas pocas semanas debido por las complicaciones que presenta, como el vasoespasmo y el edema cerebrales junto con la hiperglucemia. La hiperglucemia podría estar relacionada con el desarrollo del vasoespasmo y el edema cerebrales. Es posible que el control de la glucemia juegue un papel central en la evolución y el desenlace de la HSAa. Se han descrito los mecanismos por los cuales puede darse esta relación, que incluyen el equilibrio de iones, la liberación de aminoácidos excitadores, la estimulación de moléculas vasoconstrictoras y la disminución en la síntesis de vasorrelajantes. Sin embargo, existen estudios que no apoyan la hipótesis sobre la participación de la hiperglucemia en esta enfermedad. En conjunto, estas evidencias sugieren que el control de los niveles de glucosa podría modificar el desenlace de los grupos de pacientes con HSAa dependiendo de las complicaciones que presenten.

Aneurysmal subarachnoid hemorrhage (aSAH) may have a fatal outcome after a few weeks from ictus, due to its complications, like cerebral vasospasm and edema along with hyperglycemia. Hyperglycemia may be involved in the development of brain vasospasm and edema. It is possible that hyperglycemia plays a central role in the outcome of aSAH. Several mechanisms may explain this relationship; they include ion balance, excitatory amino acid release, stimulation of vasoconstrictor molecules and reduced synthesis of vasorelaxants. However, some studies do not support this hypothesis regarding the role of hyperglycemia in aSAH. Taken together, the evidence suggests that the control of glucose levels may influence the aSAH outcome depending on the complications that may develop.

IL-10 and ET-1 as biomarkers of rheumatic valve disease / IL-10 e ET-1 como biomarcadores de doença valvar reumática

Objective: To evaluate the immunological profile and gene expression of endothelin-1 (ET-1) in mitral valves of patients with rheumatic fever originated from a reference service in cardiovascular surgery. Methods: This was a quantitative, observational and cross-sectional study. Thirty-five subjects (divided into four groups) participated in the study, 25 patients with chronic rheumatic heart disease and ten control subjects. The mean age of the sample studied was 34.5 years. Seventeen of them (48.58%) were male and 18 (51.42%) were female. Inflammatory cytokines (TNF-α, IL-4 and IL-10) were measured and ten mitral valves of patients who underwent first valve replacement were collected for determination of gene expression of endothelin-1 by real time PCR. Results: Among the groups studied (patients vs. controls), there was a statistically significant difference in IL-10 levels (P=0.002), and no differences in other cytokines. Expression of endothelin-1 was observed in 70% of samples. Quantitatively, average of ET-1 expression was 62.85±25.63%. Conclusion: Inflammatory cytokine IL-10 participates in the maintenance of chronicity of rheumatic fever in patients who underwent valve replacement and those who are undergoing medical treatment. The expression of endothelin-1 in heart valve lesions in patients undergoing mitral valve replacement confirms its association with inflammatory activity in rheumatic fever. .

Objetivo: Avaliar o perfil imunológico e a expressão gênica de endotelina-1 em valvas mitrais de pacientes com febre reumática, originados de um serviço de referência em cirurgia cardiovascular. Métodos: Este foi um estudo quantitativo, observacional e transversal. Trinta e cinco indivíduos (divididos em quatro grupos) participaram do estudo, 25 deles com doença cardíaca reumática crônica, além de 10 controles. A média de idade da amostra estudada foi de 34,5 anos. Dezessete (48,58%) dos indivíduos eram homens, e 18 (51,42%) eram mulheres. Foram medidas algumas citocinas inflamatórias (TNF-α, IL-4 e IL-10) e coletadas 10 valvas mitrais de pacientes que se submeteram a primeira troca valvar para determinação da expressão gênica de endotelina-1 pelo PCR real-time. Resultados: Entre os grupos estudados (pacientes e controles), observou-se diferença estatisticamente significante em relação aos níveis de IL-10 (P=0,002), sem diferenças nas outras citocinas. Em relação à endotelina-1, foi observada sua expressão em 70% das amostras. Quantitativamente, a expressão média de endotelina-1 foi de 62,85±25,63%. Conclusão: A citocina inflamatória IL-10 participa da manutenção da cronicidade da febre reumática em pacientes que se submeteram a troca valvar e naqueles que estão em tratamento médico. A expressão de endotelina-1 nas lesões em valvas cardíacas de pacientes que foram submetidos à troca valvar mitral confirma sua relação com a atividade inflamatória na febre reumática. .

Big endotelina-1 e óxido nítrico em pacientes idosos hipertensos com e sem síndrome da apneia-hipopneia obstrutiva do sono / Big endothelin-1 and nitric oxide in hypertensive elderly patients with and without obstructive sleep apnea-hypopnea syndrome

FUNDAMENTO: O papel do estresse oxidativo em pacientes idosos hipertensos com síndrome de apneia-hipopneia obstrutiva do sono (SAHOS) é desconhecido. Objetivo: O objetivo foi avaliar os níveis de Big Endotelina-1 (Big ET-1) e Óxido Nítrico (NO) em pacientes idosos hipertensos com e sem SAHOS moderada a grave. MÉTODOS: Os voluntários permaneceram internados durante 24 horas. Obtivemos os seguintes dados: índice de massa corporal (IMC), Monitorização Ambulatorial da Pressão Arterial (MAPA) - 24 horas, e medicação atual. Sangue arterial foi coletado às 7:00 h e às 19:00 h para determinar níveis plasmáticos de NO e Big ET-1. A oximetria de pulso foi realizada durante o sono. A correlação de Pearson, Spearman e análise de variância univariada foram utilizadas para a análise estatística. RESULTADOS: Foram estudados 25 sujeitos com SAHOS (grupo 1) e 12 sem SAHOS (grupo 2), com idades de 67,0 ± 6,5 anos, 67,8 ± 6,8 anos, respectivamente. Não foram observadas diferenças significativas entre os grupos em IMC; no número de horas de sono; PA diastólica e sistólica em 24 h; PA de vigília; PA no sono; ou medicamentos usados para controlar a PA. Não foram detectadas diferenças nos níveis de NO e Big ET-1 plasmáticos às 19:00 h, mas às 7:00 h os níveis de de Big ET-1 foram mais altos (p = 0,03). No grupo 1, correlação negativa também foi observada entre a saturação de oxihemoglobina arterial média e a PA sistólica - 24 horas (p = 0,03, r = -0,44), e Big ET-1 (p = 0,04, r = 0,41). CONCLUSÕES: Na comparação entre idosos hipertensos com e sem SAHOS com PA e IMC semelhantes, observou-se níveis mais elevados de Big ET-1 após o sono no grupo SAHOS. Os níveis de NO não diferiram entre os pacientes hipertensos com ou sem SAHOS.

BACKGROUND: The role of oxidative stress in hypertensive elderly patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) is unknown. OBJECTIVE: The purpose was to evaluate the levels of big endothelin-1 (Big ET-1) and nitric oxide (NO) in elderly hypertensive patients with and without moderate to severe OSAHS. METHODS: Volunteers were hospitalized for 24 h. We obtained the following data: body mass index (BMI); 24-ambulatory blood pressure monitoring; and current medication. Arterial blood was collected at 7pm and 7am for determining plasma NO and Big ET-1 levels. Pulse oximetry was performed during sleep. Pearson's or Spearman's correlation and univariate analysis of variance were used for statistical analysis. RESULTS: We studied 25 subjects with OSAHS (group 1) and 12 without OSAHS (group 2) aged 67.0 ± 6.5 years and 67.8±6.8 years, respectively. No significant differences were observed between the groups in BMI; number of hours of sleep; 24-h systolic and diastolic BPs; awake BP, sleep BP and medications to control BP between groups. No differences were detected in plasma Big ET-1 and NO levels at 19:00 h, but plasma Big ET-1 levels at 7:00 h were higher in group 1 (p =0.03). In group 1, a negative correlation was also observed between the mean arterial oxyhemoglobin saturation level, 24-h systolic BP (p = 0.03, r = -0.44), and Big ET-1 (p = 0.04, r = -0.41). CONCLUSIONS: On comparing elderly hypertensive patients with and without OSAHS having similar BP and BMI, we observed higher Big ET-1 levels After sleep in the OSAHS group. NO levels did not differ between the hypertensive patients with or without OSAHS.

The effect of serum magnesium levels and serum Endothelin-1 levels on bone mineral density in protein energy malnutrition / Efecto de los niveles séricos de magnesio y los niveles séricos de Endotelina-1 sobre la densidad mineral osea en la malnutrición calórico-proteica

An inadequate and imbalanced intake of protein and energy results in protein-energy malnutrition (PEM). It is known that bone mineral density and serum magnesium levels are low in malnourished children. However, the roles of serum magnesium and endothelin-1 (ET-1) levels in the pathophysiology of bone mineralization are obscure. Thus, the relationships between serum magnesium and ET-1 levels and the changes in bone mineral density were investigated in this study. There was a total of 32 subjects, 25 of them had PEM and seven were controls. While mean serum ET-1 levels of the children with kwashiorkor and marasmus showed no statistically significant difference, mean serum ET-1 levels of both groups were significantly higher than that of the control group. Serum magnesium levels were lower than normal value in 9 (36%) of 25 malnourished children. Malnourished children included in this study were divided into two subgroups according to their serum magnesium levels. While mean serum ET-1 levels in the group with low magnesium levels were significantly higher than that of the group with normal magnesium levels (p < 0.05), mean bone mineral density and bone mineral content levels were significantly lower (p < 0.05). In conclusion, many factors play a role in the pathophysiology of changes in bone mineral density in malnutrition. Our study suggested that lower magnesium levels and higher ET-1 levels might be important factors in changes of bone mineral density in malnutrition. We recommend that the malnourished patients, especially with hypomagnesaemia, should be treated with magnesium early.

El consumo inadecuado y desbalanceado de proteínas y calorías energía conduce a la malnutrición calórico-proteica (MCP). Se sabe que la densidad mineral ósea y los niveles séricos de magnesio son bajos en los ninos malnutridos. Sin embargo, no está claro el papel que desempenan los niveles séricos de magnesio y los niveles séricos de endotelina-1 (ET-1) en la patofisiología de la mineralización del hueso. Por consiguiente, las relaciones entre los niveles séricos de magnesio y los niveles séricos de ET-1, y los cambios en la densidad mineral ósea, constituyen el objeto de investigación de este estudio. Hubo un total de 32 sujetos; 25 de ellos tenían DCP y 7 eran considerados. Si bien los niveles séricos promedios de ET-1 de los ninos con kwashiorkor y marasmo no mostraron diferencia estadística significativa, los niveles séricos promedio de ET-1 de ambos grupos fueron significativamente más altos que los del grupo de control. Los niveles séricos de magnesio estuvieron por debajo del valor normal en 9 (36%) de 25 ninos malnutridos. Los ninos malnutridos incluidos en este estudio fueron divididos en dos sub-grupos según sus niveles de magnesio en suero. Mientras que los niveles séricos promedio de ET-1 en el grupo con niveles bajos de magnesio fueron significativamente más altos que los del grupo con niveles normales de magnesio (p < 0.05), la densidad mineral ósea promedio y los niveles promedio del contenido mineral óseo fueron significativamente más bajos (p < 0.05). En conclusión, muchos factores juegan un papel en la patofisiología de los cambios en la densidad mineral ósea por la malnutrición. Nuestro estudio sugirió niveles más bajos de magnesio y niveles más altos de ET-1 podrían ser factores importantes en los cambios de densidad mineral ósea en la malnutrición. Se recomienda que los pacientes malnutridos, especialmente a causa de hipomagnesemia, sean tratados con magnesio lo más pronto posible.

Avaliação da capilaroscopia usando Endotelina-1 como um marcador de ativação endotelial na lesão microvascular e úlceras cutâneas / Evaluation of the capillaroscopy using endothelin-1 as a marker of endothelial activation in microvascular injury and cutaneous ulcerations

OBJETIVO: Avaliar a presença da ET-1 em pacientes portadores de esclerodermia e a sua correlação com o nível de atividade da doença; verificar se os níveis de endotelina estão associados com o perfil clínico e de autoanticorpos da esclerodermia e, ainda, se há associação com lesão microvascular detectada pela capilaroscopia periungueal. MÉTODOS: Um total de 74 pacientes, sendo 37 portadores de esclerodermia e o restante controle, foram submetidos à dosagem de ET-1 por meio de teste de ELISA. Pacientes com esclerodermia foram analisados através de um questionário sobre características da doença e pesquisa de autoanticorpos. A gravidade da doença foi definida pelos critérios de Medsger e a doença microvascular foi acessada através de capilaroscopia periungueal. RESULTADOS: Dos 37 pacientes com esclerodermia três (8,1%) eram homens e 34 (91,89%) mulheres, com idade média de 48,97 ? 13,36 anos e tempo médio de doença de 42,54 ? 13,35 anos. Os valores da ET-1 nos controles foram de 0,41 a 5,65 pg/ml (mediana de 2,26 pg/ml) e nos com esclerodermia de 0,41 a 8.82 pg/ml (mediana de 0,41 pg/ml) com p de 0,0007. Não houve correlação com o tempo de doença, idade do paciente e com o nível de acometimento cutâneo. Não encontrou-se correlação entre nível de ET-1 sérica e gravidade da doença (p=0,13). Níveis maiores de ET-1 foram observados na forma de superposição (1,49 a 6,82 pg/ml). CONCLUSÃO: Os níveis de ET-1 em esclerodérmicos mostraram-se inferiores aos controles. Não houve associação dos níveis de ET-1 com as variáveis estudadas.

Objectives: To evaluate the presence of ET-1 in patients with scleroderma and its correlation with the level of disease activity; to verify if the levels of endothelin are associated with the clinical profile and autoantibodies of scleroderma, and even if there is an association with microvascular injury detected by nailfold capillaroscopy. METHODS: A total of 74 patients, 37 patients with scleroderma, the remaining being controls, were subjected to measurement of ET-1 by ELISA. Patients with scleroderma were evaluated through a questionnaire about characteristics of the disease and determination of autoantibodies. Disease severity was defined by the criteria of Medsger and microvascular disease was accessed through nailfold capillaroscopy. RESULTS: Of the 37 patients with scleroderma, three (8.1%) were men and 34 (91.89%) women, with a mean age of 48.97 ± 13.36 years and mean disease duration of 42.54 ± 13, 35. The amounts of ET-1 in the controls was 0.41 to 5.65 pg / ml (median of 2.26 pg / ml) and, in the scleroderma group, from 0.41 to 8.82 pg / ml (median, 0.41 pg / ml), with p = 0.0007. There was no correlation with disease duration, patient age and the degree of skin involvement. No correlation was found between serum levels of ET-1 and disease severity (p = 0.13). Higher levels of ET-1 were observed in the form of overlap (1.49 to 6.82 pg / ml). CONCLUSION: The levels of ET-1 in scleroderma were inferior to controls. There was no association of ET-1 levels with the variables studied.

Acciones de endotelina 1 y angiotensina II en embarazos complicados con preeclampsia / Endothelin 1 and angiotensin II in preeeclampsia

Introduction. It is generally thought that development of hypertension in preeclampsia (PE) is due to generalized endothelial dysfunction and/or results from an imbalance in the production and/or action of vasoactive factors, resulting in higher citosolic Ca2+ concentration which in turn leads to vasoconstriction and decreased blood pressure perfusion in organs, including the fetoplacental unit. Among vasoactive factors involved in blood pressure regulation, endothelin 1 (ET-1) and angiotensin II (Ang II) regulate citosolic Ca2+ concentrations and therefore are considered in this review. PE is associated with higher circulating and placental ET-1 levels, observation that explains, at least in part, vasoconstriction and oxidative stress. Higher and lower Ang II sensitivity seen in PE and normal pregnancy, respectively, could not be explained by changes in renin-angiotensin system components, including Ang II receptors (ATI). During normal pregnancy, ATI receptors are found as monomers and are inactivated by reactive oxygen species (ROS) leading to lower Ang II sensitivity. In contrast, PE is associated with increased ATl/bradicinin receptors (B2) heterodimers which are resistant to inactivation by ROS, maintaining increased ATI-receptor stimulated signaling in PE. In adittion, AT-1 agonistic antibodies (AT1-AA) obtained from PE women increases intracellular Ca2+, NADPH oxidase components and ROS, effects not observed with normal pregnancy AT1-AA. Conclusion. High ET-1 levels, the presence of AT1/B2 receptor heterodimers and increased AT1-AA are involved, at least in part, in the hypertensive and oxidative stress states in PE.

Introducción. Se reconoce que el desarrollo de la hipertensión en la preeclampsia (PE) resulta del daño endotelial generalizado y/o de la falta de equilibrio en la producción y/o acción de agentes vasoactivos, lo que conlleva al incremento en la concentración citosólica de Ca2+ que resulta en vasoconstricción y disminución de la perfusión sanguínea en los órganos, incluyendo la unidad fetoplacentaria. Dentro de los factores vaso-activos que regulan la presión arterial, en la presente revisión se consideró a la endotelina 1 (ET-1) y a la angiotensina II (Ang II), factores que regulan la concentración citosólica de Ca2+. En comparación con el embarazo normal, la PE se asocia con mayor concentración en suero y placenta de ET-1, lo que explica en parte la vasoconstricción y el estado de estrés oxidativo. La respuesta exagerada en la PE y el estado de refractariedad en el embarazo normal a la Ang II no pueden explicarse por componentes del sistema renina-angiotensina, incluyendo a los receptores de Ang II (ATI). Durante el embarazo normal los receptores AT-1 se encuentran en forma de monómeros y son inactivados por las especies reactivas de oxígeno (ROS), lo que se asocia con menor respuesta a Ang II. En cambio, la respuesta exagerada a la Ang II durante la PE puede deberse a la heterodimerizacion de los receptores ATI con los de bradicinina (B2), estado que les confiere resistencia a la inactivación por las especies reactivas de oxígeno (ROS), lo que explica el incremento en la concentración del Ca2+ intracelular. Además, los anticuerpos agonistas del receptor ATI (AT1-AA) de mujeres PE aumenta la concentración de Ca2+ intracelular, de la NADPH oxidasa y de ROS, efectos que no se presentan al utilizar AT1-AA de embarazadas normotensas. Conclusión. Las altas concentraciones de ET-1, la presencia de receptores ATI en forma de heterodimeros ATI/ B2 y el aumento en los AT1-AA explican en parte, el estado de hipertensión y de estrés oxidativo de la PE.