Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A hipertensão é uma das mais importantes causas de morte prematura no mundo. Estudos sobre a Euterpe oleracea Mart. (açaí), uma planta típica do Brasil e rica em polifenóis, têm mostrado grande potencial terapêutico contra a hipertensão, uma vez que seus benefícios podem ser associados às ações antioxidante, vasodilatadora e anti-hipertensiva. O rato espontaneamente hipertenso (SHR) é um modelo experimental utilizado para o estudo da hipertensão essencial. Neste estudo, investigamos o efeito do tratamento crônico do extrato hidroalcoólico do caroço de açaí (ASE) sobre a hipertensão de SHR. Animais SHR e Wistar receberam tratamento com ASE (200 mg/Kg/dia) na água de beber, ou veículo, desde 21 dias até 4 meses de idade e tiveram a pressão arterial sistólica (PAS) aferida por pletismografia de cauda. Os efeitos vasodilatadores da acetilcolina (ACh) e nitroglicerina (NG) foram estudados em leito arterial mesentérico (LAM) perfundido e pré-contraído com norepinefrina. A atividade das enzimas superóxido dismutase (SOD), catalase (CAT), glutationa peroxidase (GPx), os níveis de malondialdeído (MDA), a carbonilação de proteínas e os níveis de nitrito foram avaliados em plasma, LAM, coração e rim por espectrofotometria. A expressão das proteínas SOD e eNOS foram avaliadas por western blot em LAM e as alterações vasculares pela espessura da túnica média em aorta. A PAS foi maior (p<0.05) nos animais SHR, e reduzida pelo tratamento com ASE. O efeito vasodilatador reduzido da ACh em SHR foi recuperado pelo ASE e o da NG não foi diferente entre os grupos. Não houve diferença nos níveis de glicose e insulina em SHR comparados aos controles. Entretanto, a insulina se apresentou reduzida no grupo SHR+ASE. O nível de renina foi maior nos SHR e normalizado pelo ASE (p<0.05). Os níveis de MDA não foram diferentes entre SHR e controles, entretanto o tratamento com ASE reduziu esses níveis em rim de SHR (p<0.05). Os níveis de carbonilação de proteínas foram maiores em amostras de rim e coração de SHR e o ASE reduziu o dano sobre proteínas (p<0.05), não tendo diferença em plasma e LAM. A atividade da SOD foi menor em amostras de rim nos animais SHR e aumentada pelo tratamento com ASE (p<0.05). Entretanto, a atividade aumentada da SOD em coração e LAM dos SHR, foi reduzida pelo tratamento com ASE, não havendo diferença em amostras de plasma. Não houve diferença na atividade da GPx em amostras de LAM e coração dos diferentes grupos, porém sua atividade foi aumentada em rim dos SHR, e o tratamento com ASE normalizou essa atividade. Em plasma, a atividade da GPx foi reduzida em SHR e aumentada pelo tratamento (p<0.05). A atividade da enzima CAT foi reduzida em plasma e rim de SHR e o ASE aumentou sua atividade. Não houve diferença em amostras de LAM, entretanto em amostras de coração o tratamento aumentou a atividade da CAT em SHR (p<0.05). Em amostras de plasma, coração e rim, não houve diferença nos níveis de nitrito entre os diferentes grupos, porém em amostras de LAM foram menores em SHR e SHR+ASE (p<0.05). A expressão das proteínas eNOS e SOD apresentaram-se aumentadas em SHR (p<0.05) sem alteração com o tratamento. Os SHR apresentaram um aumento na espessura da camada média da aorta que foi reduzido (p<0.05) pelo ASE. Este estudo demonstrou que o tratamento crônico com ASE em SHR reduziu a hipertensão, preveniu a disfunção endotelial e o remodelamento vascular. O aumento da defesa antioxidante e redução do dano oxidativo devem contribuir para os efeitos benéficos de ASE. Portanto, sugerimos que o ASE pode ser uma ferramenta importante para o tratamento das alterações cardiovasculares associadas à hipertensão essencial. / Hypertension is a major cause of premature death worldwide. Studies on the Euterpe oleracea Mart. (açaí), a typical plant of Brazil, rich in polyphenols, have shown great therapeutic potential against hypertension, since its benefits can be associated with antioxidant action, vasodilator and antihypertensive. The spontaneously hypertensive rat (SHR) is an experimental model used for the study of essential hypertension. Therefore, this study investigated the effect of chronic treatment of hydroalcoholic extract of stone of the açaí (ASE) on hypertension in SHR. For this purpose, SHR and Wistar rats were treated with ASE (200 mg.kg-1.day-) in drinking water, or vehicle, from 21 days to 4 months of age and had their systolic blood pressure (SBP) measured by tail plethysmography. The vasodilatory effects of acetylcholine (ACh) and nitroglycerin (NG) were studied in perfused mesenteric arterial bed (LAM) pre-contracted with norepinephrine. The activity of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), levels of malondialdehyde (MDA), protein carbonylation and nitrite were evaluated in plasma, LAM, heart and kidney by spectrophotometry. The expression of eNOS and SOD protein were evaluated by western blot and vascular changes by the thickness of the tunica media in aorta. SBP was higher (p <0.05) in SHR, and reduced by treatment with ASE. The reduced vasodilator effect of ACh in SHR was recovered by ASE and of the NG was not different between groups. There was no difference in the levels of glucose and insulin in SHR compared to controls. However, insulin was reduced in the SHR+ASE group. The level of renin was higher in SHR and normalized by the ASE (p <0.05). MDA levels were not different between SHR and controls, however treatment with ASE reduced these levels in kidney samples of SHR (p <0.05). The levels of protein carbonylation were higher in samples of kidney and heart of SHR and the protein damage was reduced by treatment with ASE (p <0.05), with no difference in plasma samples and LAM. The SOD activity was lower in samples of kidney in SHR and increased by treatment with ASE (p <0.05). However, the increased activity of SOD in samples of heart and LAM of SHR was reduced by treatment with ASE, with no difference in plasma. There was no difference in GPx activity in samples of LAM and hearts of different groups, but its activity was increased in kidney of SHR, and ASE treatment normalized this activity. In plasma GPx activity was reduced in SHR and increased by treatment (p <0.05). The CAT enzyme activity was reduced in samples of plasma and kidney of SHR and ASE increased its activity. There was no difference in samples of LAM, but in samples of heart treatment increased the activity of CAT in SHR (p <0.05). In plasma samples, heart and kidney, there was no difference in nitrite levels between different groups, but it was reduced in samples of LAM of SHR and SHR+ASE (p <0.05). The expression of eNOS and SOD protein was increased in SHR (p <0.05) and unchanged by treatment. The SHR exhibited an increase in medial thickness of the aorta which was reduced (p <0.05) by ASE. This study showed that chronic treatment with ASE reduced hypertension in the SHR and prevented the endothelial dysfunction and vascular remodeling. The increase in antioxidant defense and reduction of oxidative damage may contribute to the beneficial effects of ASE. Therefore, we suggest that the ASE can be an important tool for the treatment of cardiovascular disorders associated with essential hypertension.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A apneia obstrutiva do sono (AOS) é considerada um fator de risco independente para as doenças cardiovasculares. Existem evidências de que indivíduos com apneia obstrutiva do sono podem apresentar elevação nos mediadores inflamatórios, alterações no perfil metabólico, aumento na atividade do sistema nervoso simpático, com consequente elevação da pressão arterial e disfunção endotelial. Nos últimos anos, inúmeros estudos tem apontado a AOS como um dos fatores responsáveis pela hipertensão resistente. O objetivo do estudo foi avaliar a presença da apneia obstrutiva do sono e o comportamento da função endotelial em pacientes com hipertensão resistente, comparando com hipertensos apresentando pressão arterial controlada com até 3 classes diferentes de fármacos anti-hipertensivos. Trata-se de um estudo transversal com 40 pacientes hipertensos: 20 com hipertensão arterial resistente (HAR) e 20 com pressão arterial controlada por medicação (hipertensão arterial controlada; HAC), sem distinção de raça ou gênero, com idade entre 18 e 75 anos. A pressão arterial casual e a monitorização ambulatorial da pressão arterial foram aferidas por método oscilométrico em aparelhos automáticos. A função endotelial e a presença da apneia obstrutiva do sono foram avaliadas através da tonometria arterial periférica pelos equipamentos Endo-PAT2000 e o aparelho portátil Watch-PAT200, respectivamente. A avaliação antropométrica foi realizada através das aferições das circunferências da cintura e do pescoço, índice de massa corporal (IMC), e relação cintura-estatura. A composição corporal foi avaliada por bioimpedância elétrica BIODYNAMICS 450. As análises estatísticas foram realizadas pelo software GraphPad PRISM, versão 6.01. A prevalência de AOS no grupo com HAR foi de 85% (Índice de apneia-hipopneia [AHI]= 12,391,89) e de 80% no grupo com HAC (AHI =20,744,69), sendo mais frequente em homens (p=0,04; OR=3,86; 95% IC 0,99 a 14,52). Os dois grupos apresentaram valores semelhantes das variáveis antropométricas avaliadas. A função endotelial avaliada pelo índice de hiperemia reativa foi similar nos dois grupos (grupo HAR: 1,880,09 vs. grupo HAC: 2,030,09; p=0,28). Apesar do número de dessaturações de oxigênio >4% ter apresentado diferença significativa entre os grupos (grupo HAR: 28,755,08 vs. grupo HAC: 64,1516,97; p=0,04), o tempo total de sono (grupo HAR: 309,515,27 vs. grupo HAC: 323,318,74 min) e a saturação mínima da oxi-hemoglobina (grupo HAR: 87,80,85 vs. grupo HAC: 83,32,37%) não mostraram essa diferença. Considerando todos os pacientes hipertensos, o AHI apresentou correlação significativa com o peso corporal (r=0,51; p=0,0007), o IMC (r=0,41; p=0,007), a circunferência da cintura (r=0,44; p=0,005), a circunferência do pescoço (r=0,38; p=0,01) e a relação cintura-estatura (r=0,39; p=0,01). Os pacientes sem AOS em comparação com os pacientes com AOS, apresentaram risco significativamente menor de apresentar comprometimento da função endotelial (OR=0,17; 95% IC 0,04-0,72; p=0,03). Os achados do presente estudo sugerem que a prevalência de AOS em pacientes com hipertensão resistente é elevada, porém semelhante a de indivíduos com hipertensão controlada. Pacientes com hipertensão resistente e controlada não apresentaram diferenças significativas em relação à função endotelial. A gravidade de AOS no grupo total de hipertensos se associou com maior risco de comprometimento da função endotelial. / Obstructive sleep apnea (OSA) is considered an independent risk factor for cardiovascular disease. There is evidence that individuals with OSA may have increased inflammatory mediators, changes in the metabolic profile, increased sympathetic activity with consequent elevation of blood pressure (BP) and endothelial dysfunction. Resistant hypertension (RH) is defined as uncontrolled blood pressure (BP &#8805; 140/90mmHg) despite the current use of three hypotensive drugs at full doses, including a diuretic, or the need for >3 medications to control BP. OSA has been reported as the most common secondary cause of high blood pressure maintenance. The objective was to determine the prevalence of OSA and verify its association with endothelial function and anthropometric parameters in patients with resistant hypertension (RHGroup) and BP controlled by medication (CHGroup). It was a cross-sectional study involving 40 hypertensive patients (20 in RHG and 20 in CHG), aged between 18 and 75 years. Endothelial function and OSA were assessed by peripheral arterial tonometry. BP was measured by oscillometric method on automatic device. Endothelial function was assessed by peripheral arterial tonometry (PAT) by EndoPAT2000 and the OSA diagnosis also through PAT, using the portable device WatchPAT200. Anthropometric evaluation was performed through measurements of waist (WaC), hip and neck circumference (NC), BMI, waist to height ratio (WHtR), and body composition assessed by bioelectrical impedance. Patients were generally late middle-aged (54.95 2.39 in the RH group and 56.15 2.42 in the controlled hypertension [CH] group. The prevalence of OSA in RHG was 85% (17 of 20) [apnea-hypopnea index=12.391.89], and 80% (16 of 20) in CHG (AHI=20.744.69) and it was more frequent in men (93.7% [15 of 16] vs 75% [16 of 24]; p=0.04, OR=3.86; 95% IC 0.99 to 14.92). Both groups presented similar anthropometric parameters values. Endothelial function evaluated by reactive hyperemia index was similar in both groups (RHG: 1.880.09 vs CHG: 2.030.09; p=0.28). Although we found differences in oxygen desaturation> 4% (RHG: 28.75 5.08 vs CHG: 64.15 16.97, p = 0.04), total sleep time (RHG: 309.5 15.27 vs CHG: 323.3 18.74 min) and minimum saturation (RHG: 87.80.85 vs CHG: 83.32.37%) was not different. In general, OSA was correlated with weight (r = 0.51, p = 0.0007), BMI (r = 0.41, p = 0.0078), WaC (r = 0, 44, p = 0.005), NC (r = 0.38, p = 0.01) and WHtR (r = 0.39, p = 0.01) and independently associated with impairment of endothelial function (p = 0.0297, OR = 0.17, 95% CI 0.04 to 0.72). In conclusion, the findings of this study show high prevalence of OSA in patients with resistant hypertension, similar to that of controlled hypertension group. There were no significant differences in endothelial function between resistant and controlled hypertension patients. The presence of OSA in the total group of hypertensive patients was associated with increased risk of impaired endothelial function.

O Diabetes Mellitus tipo 1 (DM1) está associado a uma incidência aumentada de doença micro e macrovascular. Estudos sugerem que a doença vascular no DM1 tenha como evento precursor a disfunção endotelial (DE). A hiperglicemia parece causar DE no DM1 através da geração do estresse oxidativo. O momento exato do surgimento da DE na história natural do DM1, assim como a influência do controle glicêmico de curto e longo prazo ainda não estão estabelecidos. Objetivo: O objetivo principal do presente estudo foi avaliar a função endotelial através da Dilatação Arterial Mediada por Fluxo (DMF) em indivíduos com Diabetes Mellitus tipo1. Os objetivos secundários foram analisar os fatores que possam estar envolvidos com a disfunção endotelial no DM1, como o tempo de diabetes, o controle glicêmico e a presença de complicações microvasculares, como a microalbuminúria. Métodos: Estudo prospectivo transversal com 57 pacientes com DM1 e 10 indivíduos não diabéticos, consecutivamente alocados e comparados quanto à presença de DE, através da DMF, aferida pela dilatação da artéria braquial após hiperemia reativa (dilatação endotélio-dependente) e após dilatação mediada por uso de nitrato sublingual (dilatação endotélio-independente). Considerou-se como DE quando valores de DMF foram menores ou iguais a 8% em relação ao valor basal. Os pacientes foram orientados a fazer monitorização glicêmica capilar intensiva nos 30 dias que antecederam a avaliação vascular. No 30º dia, houve coleta de exames laboratoriais e a avaliação vascular foi realizada. Dados prospectivos e históricos de hemoglobina glicosilada (HbA1c), através da técnica de imunoturbidimetria (Cobas Integra 400; Roche), foram obtidos aos 3, 6, 9,12,15,18 e 24 meses anteriores ao teste para DMF. Os critérios de exclusão foram: tabagismo, hipertensão, obesidade, hipotireoidismo, uso de estatina, gestação, história de neoplasia ou doença vascular. Resultados: Em 57 pacientes com DM1 estudados, 28 (49%) apresentaram DE. A média da dilatação endotélio-dependente foi significativamente menor nos pacientes com DM1, comparados aos indivíduos não-diabéticos (9,48±6,48% vs.14,56±5,60%, p=0,02). A dilatação endotélio-independente foi significativamente menor nos pacientes com DM1 em relação aos controles (22,26±9,2% vs. 29,31±4,2%, p=0,02, VR: acima de 8%), mas não houve diferença entre os DM1 com ou sem DE (p= 0,72). O tempo de DM1 (meses) foi maior nos pacientes com DE do que nos sem DE (105,4±74,7 vs. 66,3±48,0, p=0.02) e houve correlação linear negativa entre duração do DM e presença de DE (r-0,28, p=0,02). A média da HbA1c (%) coletada no momento da avaliação vascular foi semelhante entre pacientes com DM1 com DE e sem DE (8,97%±1.85 vs 8,23%±1.45, p=0.10) e não houve correlação significativa com a DMF (r=-0,128 p=0,34). Todavia, quando as HbA1c históricas foram avaliadas, houve correlação significativa com a HbA1c aos 15 meses (r=-0,303, p=0,02) e no período de 12-24 meses anteriores ao exame vascular (r=-0,289, p=0,03), mas não com a HbA1c média de 0-12m (r=-0,181 p=0,18). A DMF foi menor nos pacientes com microalbuminúria em relação aos normoalbuminúrcos (4,83±3,81% vs 10,35±6,50%, p=0,015). A microalbuminúria também foi mais prevalente nos DM1 com DE do que sem DE (22,2% vs 3,5%, p=0,04). Considerando apenas os pacientes com DM1 com tempo de DM menor que 5 anos, 10/28 (35,7%) apresentaram DE. Com relação a dilatação não-dependente de endotélio (%), não houve diferença em relação aos controles (p=0,16) e nem entre os DM1 com e sem DE (p=0,27). A média da HbA1c na época do exame vascular também não foi diferente nos pacientes com e sem DE (8,20±0,94% vs. 7,99±1,37%, p=0,66). As correlações de Pearson entre a DMF e as HbA1c históricas foram negativas aos 12 meses (r=-0,419, p=0,03), aos 15 meses (r=-0,437, p=0,03) e com a HbA1c média de12-24 meses (r=-0,426, p=0,027). Conclusões: Pacientes com DM1 apresentam prejuízo na função endotelial, quando comparados a controles não diabéticos. A DE é um evento precoce na história natural do DM1, e está presente nos pacientes antes dos 5 anos de doença, estando associada, ao tempo de DM1, à presença de microalbuminúria e ao controle metabólico de longo-prazo. A ausência de disfunção de músculo liso endotelial no grupo com menos de 5 anos de DM, com valores de dilatação não-endotéliodependente semelhantes aos controles, sugere ser a DE um fenômeno ainda reversível nos primeiros anos de doença. / Patients with Type 1 diabetes (T1DM) are at high-risk for developing micro and macrovascular complications. Endothelial dysfunction (ED) has been suggested to be a precursor of both complications in Type 1 diabetes. Hyperglycemia may be associated to ED through generation of oxidative stress. The exactly moment when ED occurs in T1DM is until not well established. Also we do not known if long-term rather than short term metabolic control have a greater impact in ED. Objective: The aim of this study was to assess endothelial function by Flow Mediated Dilation (FMD) in (T1DM) patients and compare with non- diabetic controls. Secondary objectives were to analyze factors that could be associated to ED: duration of T1DM, glycemic control and microvascular complications like microalbuminuria. Research design and methods: In a cross-sectional study 57 adolescents with T1DM and 10 non-diabetic controls, were recruited and compared for the presence of ED by FMD with evaluation of reactive hyperemia (endothelium-dependent dilatation) and after using sublingual nitrate spray for assessed non-endothelialdependent dilatation. ED was considered when FMD ≤ 8% in relation to basal value. Patients performed intensive self monitoring blood glucose for 30 days before vascular studies. At day 30, blood was drawn for biochemical determinations and endothelial function was carried out. Historical data from Glycated hemoglobin (HbA1c), determined by immunoturbidimetry (Cobas Integra 400; Roche) were collected at 3, 6, 9,12,15,18 and 24 months before the test for FMD. Excluding criteria were any time tobacco use, clinical hypertension, obesity, hypothyroidism, statin use, current pregnancy and any history of previous neoplasia or vascular disease. Results: Of 57 T1DM patients studied, 28 (49%) presented ED. FMD was significantly decreased in T1DM compared to controls (9.48±6.48% vs. 14.56±5.60%, p=0.02). Nitrate-mediated dilation (%) was decreased in T1DM compared to controls (22.26±9.2% vs. 29.31±4.2%, p=0.02, RV= >8%), but it was not different between T1DM with or without ED (p=0.72). The duration of T1DM was longer in ED vs. Non- ED patients: 105.4±74.7 vs. 66.3±48.0 months, p= 0.02 and presented negative linear correlation between duration of T1DM and FMD (r=-0.284, p=0.03). HbA1c at the moment of the vascular analysis did not differ between ED and Non-ED patients (8.97±1.85% vs. 8.23±1.44%, p= 0.10) and it was not associated with FMD (r=-0.128, p=0.34). However, we found significant negative correlation between HbA1c and FMD at 15 months (r=-0.303, p=0.02) and at 12-24 months before vascular study, but not with median HbA1c of 0-12m (r=-0.181 p=0.8). Microalbuminuria was more prevalent in T1DM patients with ED than Non-ED (22.2% vs. 3.5%, p=0.04). FMD was decreased in microalbuminuric compared to normoalbuminuric patients (4.83±3.81% vs 10.35±6.50%, p=0.015). In T1DM patients with less than 5 years of disease, 10 of 28 (35.7%) presented ED. Nitrate-mediated dilation, in this group, was not decreased compared to controls (p=0.16) and it was not different in T1DM patients with or without ED (p=0.27). HbA1c at the moment of vascular analysis did not significantly differ in ED compared to Non-ED patients (8.20±0.94% vs.7.99±1.37%, p=0.66). Pearson’s correlation between FMD and historical HbA1c was negative with HbA1c at 12 (r=-0.419, p=0.03), at 15 (r=-0.437, p=0.03) and 12-24 months before vascular analysis (r=- 0.426, p=0.02). Conclusions: Endothelial function is impaired in T1DM patients compared to nondiabetic controls. ED is a phenomenon that can occur quite early in the natural history of T1DM, presented before 5 years of disease and is related to duration of disease, long- term metabolic control and microalbuminúria. Vascular smooth muscle was not impaired in T1DM patients with less than 5 years of disease, with values of non-endothelial-dependent dilation similar to controls, suggesting that ED can be a reversible event in this first years of disease.

Introdução: As doenças cardiovasculares representam a principal causa de morte no mundo, sendo o aumento da concentração de colesterol sanguíneo um dos seus principais fatores de risco. O processo aterosclerótico envolve não apenas a deposição de colesterol nas artérias, mas a inflamação tem papel central em todas as fases do processo aterosclerótico. Estudo em animais mostrou, por sua vez, que a proteína de feijão caupi é um potente redutor na concentração de colesterol sangüíneo. Objetivo: Avaliar a influência da proteína de feijão caupi sobre o perfil lipídico, apolipoproteínas, glicose, insulina, HOMA-IR, marcadores de inflamação e de disfunção endotelial em pacientes hipercolesterolêmicos. Métodos: A proteína de feijão caupi foi isolada por precipitação isoelétrica da farinha de feijão caupi desengordurada. O isolado protéico de caupi (IPC) foi utilizado no desenvolvimento do shake à base de proteína de caupi, caseinato de cálcio foi utilizado para desenvolvimento do shake controle. Realizou-se um ensaio clínico do tipo crossover, aleatorizado, cego e controlado. Uma amostra de 44 indivíduos hipercolesterolêmicos foi dividida em 2 grupos (Grupo Controle e Grupo IPC), cada grupo recebeu shake caseína e shake IPC, respectivamente, por 6 semanas cada. Depois do washout de 4 semanas, os indivíduos receberam o shake oposto por mais 6 semanas. Foram quantificadas as variáveis bioquímicas: colesterol total, LDL-c, HDL-c, triglicerídeos, colesterol não-HDL, apo A1, apo B, razão LDL/HDL, razão TG/HDL, razão apo B/apo A1, glicose de jejum, insulina de jejum, HOMA-IR (modelo de avaliação da homeostase), proteína C reativa (PCR), molécula de adesão intercelular solúvel-1 (sICAM-1) e molécula de adesão vascular solúvel-1 (sVCAM- 1) antes e após cada período experimental. A diferença entre os shakes foi analisada com ANOVA para medidas repetidas ao nível de significância de 5 por cento . Resultados: A amostra final foi composta por 38 indivíduos com idade média de 57 anos. A redução em cadeia (delta após consumo de proteína de feijão caupi menos delta após consumo de caseína) no colesterol total foi de 21,0 mg.dL-1 (p < 0,001), CT( por cento ) foi de 8,4 por cento (p < 0,001), LDL( por cento ) foi de 14,4 por cento (p < 0,001), colesterol não-HDL foi de 24,3 mg.dL-1 (p < 0,001) e apo B foi de 15,5 mg.dL-1 (p < 0,001). A ingestão de proteína de caupi afetou significativamente o HDL-c e a mudança em cadeia observada foi um aumento de 3,2 mg.dL-1 (p =0,044). Os marcadores de metabolismo glicídico (glicose de jejum, insulina de jejum e HOMA-IR), bem como os marcadores de inflamação (PCR) e de disfunção endotelial (sVCAM-1 e sICAM- 1) não sofreram modificações significativas após consumo de proteína de feijão caupi (p > 0,05). Conclusão: O presente estudo mostra que a ingestão diária de 25 g de proteína de feijão caupi durante 6 semanas é capaz de reduz os níveis de colesterol sanguíneo, em especial a fração LDL-c; no entanto, não parece exercer influência sobre os marcadores de inflamação subclínica e de disfunção endotelial. Portanto, o aumento do consumo de feijão caupi pode representar uma alternativa eficaz, barata e viável na melhora dos níveis lipídicos em indivíduos hipercolesterolêmicos / Introduction: Cardiovascular diseases are the leading cause of death worldwide, and the increase of cholesterol in blood is one of their main risk factors. The atherosclerotic process involves not only the deposition of cholesterol in the arteries, inflammation plays a central role in all stages of atherosclerosis. Animal study showed that the protein of cowpea is a potent reducer of blood cholesterol. Objective: To evaluate the influence of cowpea protein on blood lipids, apolipoproteins, glucose, insulin, HOMA-IR, markers of inflammation and endothelial dysfunction in hypercholesterolemic patients. Methods: The protein of cowpea was isolated by isoelectric precipitation of defatted flour of cowpea. Cowpea protein isolate (CPI) was used to develop the cowpea protein shake, and calcium caseinate was used for development of the control shake. A cross-over, randomized, blinded and controlled clinical trial was conducted with a sample of 44 hypercholesterolemic subjects, which was divided into two groups (control group and CPI group). Each group received casein shake and CPI shake, respectively, for taken for 6 weeks. After this period and a 4-week washout, subjects received the opposite shake for taken for 6 weeks. Biochemical variables were measured: total cholesterol, LDL-C, HDL-C, triglycerides, non-HDL cholesterol, apo A1, apo B, LDL/HDL ratio, TG/HDL ratio, apo B/apo A1 ration, fasting glucose, fasting insulin, HOMA-IR (homeostasis model assessment), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1) before and after each experimental period. The difference between the shakes was analyzed with repeated measures analysis of variance (ANOVA) at a significance level of 5 per cent . Results: The final sample consisted of 38 subjects with mean age of 57 years. The net changes in serum total cholesterol concentrations was a decrease of -21.05 mg.dL-1 (p < 0.001), in total cholesterol was -8.42 per cent (p < 0.001), in LDL-c was -14.36 per cent (p < 0.001), in non-HDL cholesterol was -24.29 mg.dL-1 (p < 0.001) and apoB was -15.55 mg.dL-1 (p < 0.001). Cowpea protein intake significantly affected serum HDL-c concentrations, the net change was a increase of 3.24 mg.dL-1 (p= 0,044). Markers of glycemic control (fasting glucose, fasting insulin and HOMA-IR) and inflammation markers (CRP) and endothelial dysfunction (sICAM-1 and sVCAM-1) have not changed significantly after consumption of cowpea protein (p > 0.05). Conclusion: This study shows that daily intake of 25 g of cowpea protein for 6 weeks can reduce levels of blood cholesterol, especially LDL-c, however did not exhibit influence on markers of subclinical inflammation and endothelial dysfunction. Therefore, the consumption of cowpea can be an effective, inexpensive and feasible way to control blood lipids of hypercholesterolemic subjects

Orientador: Ana Paula Couto Davel / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T21:17:31Z (GMT). No. of bitstreams: 1 Maia_AlineRosa_M.pdf: 2655411 bytes, checksum: 2b34ee24d63332baec9cbcda46195816 (MD5) Previous issue date: 2013 / Resumo: Introdução e objetivos: A desnutrição intrauterina e infantil predispõe a distúrbios metabólicos e cardiovasculares na idade adulta. A suplementação dietética com os aminoácidos leucina, que pode estimular a síntese proteica, ou taurina, de ação antioxidante, poderiam apresentar efeitos protetores na vasculatura nestes casos. Assim, o objetivo deste trabalho foi avaliar os efeitos da restrição proteica pós-desmame e da suplementação com leucina ou taurina sobre a pressão arterial (PA) e função vascular, enfatizando o papel do endotélio e as vias de sinalização celular envolvidas. Métodos eresultados: Ratos Wistar foram divididos, após o desmame (~21 dias de vida), em dois grupos dietéticos por 90 dias: controle (C; 12% de proteínas) e de restrição proteica isocalórica (R; 6% de proteínas). Estes receberam ou não suplementação na água de beber com taurina 2,5% (CT e RT) por 90 dias ou com leucina 1,5% (CL e RL) apenas nos 30 dias finais. O grupo R apresentou baixo ganho de peso corporal e elevação da PA sistólica (PAS), diastólica e média. A reatividade vascular foi avaliada em anéis de aorta torácica. Não houve modificação na resposta contrátil ao KCl e à fenilefrina entre os grupos estudados. Entretanto, observou-se aumento da resposta de relaxamento ao nitroprussiato de sódio (NPS) e, inversamente, redução do relaxamento induzido pela acetilcolina (ACh) no grupo R, em comparação ao C. A resposta à ACh da aorta do grupo R foi recuperada pela incubação com superóxido dismutase (SOD; 150 U/mL) ou apocinina (30 ?M). Além disso, houve redução do efeito do inibidor da fosfatidilinositol-3quinase (PI3K) LY294002 (30 ?M) sobre o relaxamento à ACh da aorta de R. Avaliou-se a expressão proteica por técnica de imunoblotting ou luminex em homogenato de aorta.Observou-se que a restrição proteica reduziu a expressão das proteínas: Ser473p(fosforilada)-Akt/Akt, Ser1177p-sintase de óxido nítrico endotelial (eNOS)/eNOS, fosfodiesterase 5 (PDE-5), SOD extracelular (EC-SOD); e aumentou a expressão da subunidade p47-phox da NADPH oxidase, Mn-SOD, Ser727p-proteína transdutora de sinal e ativadora de transcrição 3 (STAT3)/STAT3 e Thr412p-p70S6 quinase ribossomal (S6K)/S6K. Além disso, a restrição proteica aumentou a produção de espécies reativas ao oxigênio (ROS), avaliada pela quantificação da fluorescência ao di-hidroetídeo. A suplementação com leucina não recuperou o ganho de peso corporal, mas normalizou a pressão arterial, o relaxamento à ACh e ao NPS, o efeito do LY294002 e o conteúdo das proteínas Ser473p-Akt/Akt, Ser1177p-eNOS/eNOS, PDE-5, Ser727p-STAT3/STAT3 e Thr412p-S6K/S6K na aorta de RL, além de aumentar a expressão de PI3K em CL e RL. A taurina também melhorou oganho de peso, a PAS e a resposta de relaxamento à ACh no grupo RT, efeitos associados à normalização da produção de ROS, da expressão proteica de p47-phox e de EC-SOD na aorta de RT, e ao aumento de nitrito/nitrato plasmático neste grupo. Conclusões: Os dados sugerem que a restrição proteica pós-desmame causa prejuízo do relaxamento endotélio-dependente em aorta de ratos associada a: 1) diminuição da ativação da via PI3K/Akt e consequente redução da fosforilação de eNOS, recuperada pela suplementação com leucina, e 2) estresse oxidativo vascular, normalizado pela suplementação com taurina / Abstract: Background and aim: Intrauterine and child malnutrition predisposes to metabolic and cardiovascular disorders in adulthood. Dietary supplementation with leucine or taurine, through stimulating protein synthesis or presenting antioxidant activity, respectively, could have protective effects on the vasculature in this situation. Thus, the aim of this study was to evaluate the effects of post-weaning protein restriction and the supplementation with leucine or with taurine on the arterial blood pressure (BP) and vascular function, emphasizing the role of endothelium and the signaling pathways involved. Methods and results: Male Wistar rats were divided after weaning into two groups according to diet to be received for the next 90 days: control (C, 12% protein) and isocaloric protein restriction (R; 6% of proteins). Rats were supplemented or not in the drinking water with 2.5% taurine (CT and RT) for 90 days or 1.5% leucine (RL and CL) during the final 30 days. Afterwards, protein restriction induced low body weight gain and high systolic (SBP), diastolic and mean BP values. Thoracic aortic rings were isolated for vascular reactivity study. The contractile response to KCl or phenylephrine did not change among groups. However, the relaxation response to sodium nitroprusside (NPS) was enhanced, while the acetylcholine (ACh)-induced relaxation was reduced in R aortas compared with C. Both apocynin (30 ?M) or superoxide dismutase (SOD; 150 U/mL) incubation recovered the relaxation to ACh. The effect of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (30 ?M) on the ACh induced-relaxation was impaired in aorta from R. In addition, reactive oxygen species (ROS) production evaluated by fluorescence to dihydroethidium was increased in aorta from R. Immunoblotting and Luminex assay were used to evaluate protein expressions in aorta homogenates. Expression of Ser473p(phosphorylated)-Akt/Akt, Ser1177pendothelial isoform of nitric oxide synthase (eNOS)/eNOS, phosphodiesterase 5 (PDE-5) and extracellular (EC)-SOD were reduced by protein restriction while the expressions of p47-phox NADPH oxidase subunit, Mn-SOD, Ser727p-signal transducer and activator of xiii transcription protein 3 (STAT3)/STAT3 and Thr412p-ribossomal S6 kinase (S6K)/S6K were increased in aortas from R compared to C. Leucine did not change weight gain, but normalized BP values as well as the relaxation response to ACh, the effect of LY294002 and the protein expressions of Ser473p-Akt/Akt, Ser1177p-eNOS/eNOS, PDE-5, Ser727p- STAT3/STAT3 and Thr412p-S6K/S6K in RL aortas compared with R. Therefore leucine increased the expression of PI3K in both CL and RL. Taurine improved weight gain, the SBP and the ACh-induced relaxation in RT compared to R. These effects of taurine were associated with normal ROS production and p47-phox and EC-SOD protein expressions in aortas from RT, concomitant with an increase of plasma nitrite/nitrate in this group. Conclusions: The data suggest that post-weaning protein restriction impairs endotheliumdependent relaxation in rat aorta related to: 1) decreased activation of PI3K/Akt pathway and reduction of eNOS phosphorylation, that is recovered by leucine supplementation and 2) vascular oxidative stress, which is normalized by taurine supplementation / Mestrado / Fisiologia / Mestra em Biologia Funcional e Molecular

La prééclampsie est une maladie humaine qui affecte 3-8 % des grossesses dans le monde, cliniquement définie par l’apparition de novo d’une hypertension et d’une protéinurie. La cause initiale de la maladie semble être liée à un défaut de vascularisation placentaire, ce qui entraine des cycles d'hypoxie – ré-oxygénation, une ischémie placentaire et la libération de débris placentaires dans la circulation maternelle. Ces derniers sont responsables d'une activation endothéliale généralisée, exacerbée par un état pro-coagulant et pro-inflammatoire. Pour mieux caractériser la réponse des cellules endothéliales aux facteurs plasmatiques présent dans la circulation maternelle des femmes prééclamptiques , nous avons choisi une approche à l’échelle du génome entier pour évaluer le profil d'expression génique (grâce à des puces d’expression) de la lignée de cellules endothéliales humaines de la veine ombilicale (HUVEC) cultivée avec du plasma prééclamptique, comparée au profil de cellules cultivées avec du plasma humain provenant de grossesses normales. Cette étude nous a permis d'identifier différents gènes modulés dont celui codant la protéine de dimérisation Jun 2 (JDP2, diminué près de trois fois) qui pourrait être responsable d'une partie des modifications transcriptomiques trouvées. De façon intéressante en effet, inhiber JDP2 par une approche de siRNA régule significativement à la baisse (entre autres) l'expression du VEGF, imitant ainsi les effets du plasma prééclamptique sur les HUVEC. Dans la dernière partie de mon projet, nous nous sommes particulièrement concentrés sur l'impact de l’inhibition de JDP2 sur des gènes induits par l'hypoxie. La tension partielle basse en oxygène modifie l'expression génique par l'intermédiaire de la stabilisation du facteur de transcription HIF- 1a. En fait, dans un état hypoxique, HIF- 1a échappe à la dégradation par le protéasome, il forme alors des hétérodimères avec ARNT (HIF- 1ß) et induit l'expression de gènes ayant un élément de réponse à l’hypoxie (HRE) dans leur promoteur. L'induction de l'expression du VEGF dans des conditions d’hypoxie constitue un des premiers modèles de l’effet de l’hypoxie sur l’expression génique et c’est également un des mieux caractérisés. Afin d'évaluer le rôle de JDP2 sur l'expression du VEGF, et plus généralement sur des gènes cible de l’hypoxie, nous avons cultivé des cellules HUVEC dans des conditions de normoxie et d’hypoxie. Les mêmes conditions ont été utilisées en association avec la transfection de siRNA contre JDP2. En conclusion, dans des conditions d’hypoxie, l’inhibition de JDP2 a un impact négatif sur l'expression du VEGF. De plus, JDP2 semble être un médiateur essentiel de l'expression génique induite par l'hypoxie, car il est nécessaire à une activité complète de promoteur contenant des HRE (démontré dans des essais luciférase). / Preeclamspia is a unique human disorder which affects 3-8% of pregnancies worldwide, clinically defined as the new onset of hypertension and proteinuria. The root cause of the disease seems to be linked to a defect of placental vascularization, which enhances cycles of hypoxia –reoxygenantion, placental ischemia and the release of placental debris into maternal circulation. The latter ones are responsible for a widespread endothelial activation, exacerbated pro-coagulable and pro-inflammatory state. To best characterize the response of endothelial cells to the plasma factors present in maternal circulation of preeclamptic women, we chose a genome –wide approach in order to evaluate the gene expression profile of Human Umbilical Vein Endothelial Cells (HUVEC) line cultivated with preeclamptic plasma, compared to cells cultivated with human plasma coming from normal pregnancies. This study allows us to identify the gene Jun Dimerization Protein2 (JDP2) which could be responsible for part of transcriptomic modifications. Interestingly inhibiting JDP2 by the use of siRNA significantly down- regulates VEGF expression, thus mimicking the effects of preeclamptic plasma on HUVEC. In the last part of my project we focus specifically on the impact of JDP2 knock down on hypoxia- induced genes. Low oxygen tension modifies gene expression via the stabilization of the transcription factor HIF-1a. In fact under hypoxic condition, HIF-1a escapes from proteasomal degradation, it forms heterodimers with ARNT (HIF- 1ß) and induces the expression of genes having a Hypoxia Responsive Element (HRE) in their promoter. One of the first and best characterized models of the effect of hypoxia on gene expression is the induction of VEGF expression under hypoxic condition. In order to evaluate the contribution of JDP2 to VEGF expression, and more generally to hypoxia target genes, we cultivate HUVEC in normoxic and hypoxic condition. The same conditions were used in association with transfection of siRNA against JDP2. In conclusion, under hypoxic condition, JDP2 down- regulation has a negative impact on VEGF expression. Moreover, JDP2 seems to be an essential mediator of hypoxia –induced gene expression, since it is necessary for a full HRE promoter activity (demonstrated by Luciferase assays).

Doctor of Philosophy / Department of Anatomy and Physiology / Thomas J. Barstow / The overall aims of this dissertation are to determine the incidence and magnitude of insulin resistance (IR) in a cohort of normoglycemic college-age subjects with a family history of type 2 diabetes, and to ascertain if there is early macro- and microvascular dysfunction relative to IR. Study 1 (Chapter 2) revealed a 7-fold range in IR in healthy college subjects concomitant with measures of insulin, both fasted and during an oral glucose tolerance test, but not related with any measure of plasma glucose. These results emphasize that early in the etiology of carbohydrate dysregulation, abnormalities first occur with regard to insulin sensitivity. Using brachial artery blood flow (BABF, Doppler fluxometry) and near-infrared spectroscopy (NIRS) (Chapter 3) we extended the understanding of the use of these non-invasive tools to assess forearm resting metabolic rate and to compare the parameters of both the NIRS oxy-hemoglobin signal, as a index of perfusion in the microcirculation, and BABF, as an independent measure of microvascular reactivity during post occlusive reactive hyperemia (PORH). Resting metabolic rate ranged ~ 2 fold (2.83-5.15 [Mu]MO[subscript2]/min/100g) similar to direct measures. Amplitude, but not kinetic parameters for NIRS variables correlated with comparable parameters for BABF, providing evidence for the possible utility of NIRS in examining microvascular reactivity. In study 3 (Chapter 4), utilizing our extended understanding of hemodynamics garnered from the results of study 2, we assessed the influence of IR on macro- and microvascular reactivity. We observed that i) the magnitude of IR was significantly correlated with attenuation of endothelium-dependent vasodilation of the brachial artery (P< .01) indicating the possibility of a reduced nitric oxide bioavailability and an enhanced atherogenic milieu. Additionally we found ii) BABF at rest and during reactive hyperemia to be strongly correlated with conductance (reduced downstream resistance—an indicator of microvascular control abnormalities) independent of forearm metabolic rate, and iii) parameters of BABF (microvascular response) were also strongly correlated with brachial artery vasoreactivity (macrovascular response). In conclusion, this body of work furthers our insight into the need for earlier identification of "disease" earlier in the progression to type 2 diabetes, and provides direction for future investigations into prevention / intervention to improve microvessel functionality and to slow the atherosclerotic process in larger vessels.

L’obésité représente un important facteur de risque prédisposant aux complications cardiovasculaires. Au niveau vasculaire, la dysfonction endothéliale est considérée comme l’une des altérations les plus précoces de ces complications, mais qui peut cependant être corrigé par l’exercice physique. Récemment, de nombreux travaux se sont intéressés aux microparticules circulantes (MPs) qui seraient impliquées dans de nombreux mécanismes cellulaires grâce à leur contenu en protéines et en microARNs. Nous nous sommes donc proposé dans le cadre de cette thèse de nous intéresser aux rôles que pourraient jouer ces MPs circulantes au niveau vasculaire dans un contexte d’obésité et suite à un exercice physique chronique. Notre travail a consisté dans un premier temps à évaluer l’intégrité vasculaire et notamment la fonction endothéliale chez des sujets obèses et normo-pondérés. Nous avons par la suite quantifié les MPs circulantes au niveau plasmatique et évalué leurs effets sur la fonction endothéliale d’aorte de rats ex vivo. Nous avons également étudié la composition de ces MPs circulantes en protéines impliquées dans la fonction endothéliale (eNOS et NADPH oxydase). Dans un second temps, nous nous sommes intéressés à l’effet d’un programme d’exercice physique de 8 semaines au niveau vasculaire (fonction endothéliale, inflammation, stress oxydant) pour groupe de sujets sains et obèses. L’effet de l’exercice physique sur la concentration plasmatique et la composition de ces MPs en microARNs a également été évalué. Nos résultats nous ont permis de mettre en évidence une dysfonction endothéliale chez nos sujets obèses, un stress oxydant et une inflammation chronique. Les concentrations plasmatiques des MPs plasmatiques des sujets obèses étaient augmentées sans toutefois être corrélés avec les marqueurs de la dysfonction endothéliale. De plus, l’analyse fonctionnelle de ces MPs ex vivo et l’étude de leur composition nous a permis de conclure que, d’une part, ces MPs ne participaient à l’altération de la fonction endothéliale induite par l’obésité, et d’autre part, qu’elles reflétaient un mécanisme compensatoire au niveau vasculaire tendant à augmenter la biodisponibilité du NO et à contrebalancer les effets néfastes de la dysfonction endothéliale. Nous avons également pu observer que l’expression de nombreux micro-ARNs, qui seraient impliquées dans les mécanismes inflammatoires et athéroprotecteurs, étaient augmentées dans les MPs de sujets sains et obèses suite au programme d’exercice physique suggérant que ces MPs pourraient contribuer dans les effets bénéfiques de l’exercice observées au niveau vasculaire. / Obesity is a major risk factor predisposing to cardiovascular diseases. Endothelial dysfunction is considered as one of the earliest vascular alterations, but which could besides be restored by exercise. Recently, circulating microparticles (MPs) emerged as an important actor in many cellular mechanisms in the vasculature, through their protein and microRNA contain. In this thesis, we proposed to focus on these circulating MPs and their possible roles in the vasculature, in a context of obesity and in response to a chronic physical exercise. We previously evaluated vascular integrity, including endothelial function, in a population of obese and normal-weighted control group. Then, we quantified plasmatic circulating MPs and assessed their effects on endothelial function of rat aorta ex vivo. We also studied MPs composition on proteins implicated in endothelial function (eNOS and NADPH oxidase). In a second time, we interested on the effect of an 8 week training program on endothelial function and inflammatory and oxidative markers. The effect of exercise on plasmatic MPs level and their microRNAs-containing expression was also evaluated. Our results showed endothelial dysfunction, oxidative stress and inflammation in obese group. Moreover, MPs plasmatic level was enhanced for this group but were not correlated with endothelial dysfunction markers. In addition, functional analysis of obese MPs and their composition in eNOS and NADPH oxidase proteins allowed us to conclude that, firstly, these MPs are not implicated in obesity induced endothelial dysfunction and, secondly, they reflect a compensatory vascular mechanism which tends to increase nitric oxide bioavailability to offset endothelial dysfunction adverse effects. We also observed that microRNA expression, implicated in inflammatory and atheroprotective mechanisms, was enhanced in MPs of obese and normal-weighted subjects following the training program suggesting that these MPs could contribute in exercise beneficial effects.

Angiogenic cell therapy is currently being developed as a treatment for coronary artery disease (CAD); however, endothelial dysfunction (ED), commonly found in patients with CAD, impairs the ability for revascularization to occur. We hypothesized that culture on a collagen matrix will improve survival and function of circulating progenitor cells (CPCs) isolated from a mouse model of ED. Overall, ED decreased the expression of endothelial markers in CPCs and impaired their function, compared to normal mice. Culture of CPCs from ED mice on collagen was able to increase cell marker expression, and improve migration and adhesion potential, compared to CPCs on fibronectin. Nitric oxide production was reduced for CPCs on collagen for the ED group; however, CPCs on collagen had better viability under conditions of serum deprivation and hypoxia, compared to fibronectin. This study suggests that a collagen matrix may improve the function of therapeutic CPCs that have been exposed to ED.

L’augmentation constante de l’obésité dans les populations occidentales accroit la prévalence de nombreuses maladies liées au surpoids parmi lesquelles le syndrome d’apnées hypopnées du sommeil (SAHOS). Le SAHOS et l’obésité représentent deux facteurs de risque indépendants du développement de maladie cardiovasculaires (CV) et métaboliques. Etant souvent associés en pratique clinique, l’étude de leurs effets vasculaires et métaboliques spécifiques est difficile. Pour nous affranchir de cette problématique, nous avons étudié chez la souris, les effets respectifs et combinés d'un régime riche en graisse et/ou de 15 jours d'exposition à des conditions d'hypoxie intermittente (HI) mimant le SAHOS, sur les paramètres vasculaires et métaboliques. L’HI seule n'avait aucun impact sur le bilan-glucido lipidique, la fonction mitochondriale hépatique et la fonction vasculaire des animaux. Les animaux soumis au RRG présentaient une dyslipidémie,une stéatose hépatique, une dysfonction mitochondriale ainsi qu'une une dysfonction endothéliale. Lorsque l’HI était appliquée aux animaux recevant le RRG, l’ensemble de ces dysfonctions vasculaires, hépatiques et mitochondriales était prévenu mais une hyperinslinémie marquée était notée. Ce travail illustre les effets polymorphes de l’HI qui, pour des durées d’exposition courtes, pourrait présenter des effets bénéfiques sur les altérations associées à l’obésité qui contrastent avec les effets délétères à plus long terme décrits dans le SAHOS. / Decades increases the prevalence of many overweigh tassociated diseases including obstructive sleep apnea (OSA). Both OSA and obesity are considered as independent cardio-vascular and metabolic risk factors.The frequent association of OSA and obesity in clinical setting makes difficult to investigate their independent contribution to metabolic and vascular diseases. In the present thesis, we aimed to evaluate the impact of a short term intermittent hypoxia (IH), (animal model of OSA), of a high fat diet (HFD), and of both experimental conditions together (IH and HFD) on the vascular and metabolic outcomes. Short term IH alone had no impact on glucose and lipids levels and mitochondrial and vascular function. Animals fed with HFD presented dyslipidemia, hepatic steatosis, mitochondrial and endothelial dysfunction. Interestingly, when short term IH was applied to HFD fed mice, insulin level was increased, restored endothelial function and mitochondrial activity was restored and limited liver lipid accumulation was limited.Those data underline the polymorphic effects of IH that might target beneficial outcomes when applied for a short term in obesity, which contrast with the deleterious long term outcomes observed in OSA.