Atherosclerotic cardiovascular disease secondary to deposition of apolipoprotein B-containing lipoproteins in the artery wall is a leading cause of mortality. Therapies that reduce serum levels of atherogenic lipoprotein-cholesterol have been successful in reducing cardiovascular mortality, but this approach requires long-term treatment and substantial residual risk remains. Here, we investigate mechanistic determinants of atherosclerosis protection by two potential therapeutic approaches for lowering of residual cardiovascular risk. Using mouse models, we show that the nuclear receptor liver X receptor exerts an anti-inflammatory activity on innate immunity and atherosclerosis through both promotion of cholesterol efflux and a direct cis-repressive activity affecting neutrophil inflammation. We then assess the causal role of the cholesterol efflux pathway in human cardiovascular events by using genetic variants that modify high density lipoprotein-cholesterol in instrumental variable analysis. We show that this pathway is associated with protection from cardiovascular disease in a precise and robust Mendelian randomization analysis on an FDR-controlled set of variants, which suggests a causal effect. Thus, agents that target the cholesterol efflux and liver X receptor cis-repression pathways may be protective in atherosclerosis.

Context: miointimal thickening is a early vascular changes, above the sign ateromatosa. Such thickening corresponds to an early stage of atherosclerosis, which can be viewed through the B mode ultrasound; having this thickening prognostic value well demonstrated as a predictor of future vascular events. The grayscale ultrasound was used until recently as a non-invasive method pattern to identify and discriminate the composition of atherosclerotic plaque. An innovative approach of analysis of radio signals emitted by B-mode ultrasound, made possible the development of an ultrasound technique called color ultrasound tissue characterization (CATUS), this is promising in atherosclerotic vulnerable plaque detection and evaluation of his natural history; soon, prospective studies using the analysis provided by this instrument can corroborate the distinction of boards susceptible to rupture and, consequently assist in prevention of cardiovascular events. Objective: To determine the difference of ultrasound tissue characterization (CATUS) compared to B-mode ultrasonography in myointimal hyperplasia. Hypothesis: There is difference in ultrasound tissue characterization compared to B-mode ultrasonography in myointimal hyperplasia. Type of study: experimental, cross-sectional comparative study. Sample: The sample was probabilistic, for convenience, in aortas of 10 albino rabbits of the genus Oryctolagus cuniculus, belonging to New Zeland. Variable: The difference of ultrasound tissue characterization (CATUS) compared to B-mode ultrasound in myointimal hyperplasia. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Contexto: O espessamento miointimal é uma alteração vascular precoce, que precede a placa ateromatosa. Tal espessamento corresponde a um estágio inicial da aterosclerose, que pode ser visualizado por meio da ultrassonografia modo B; tendo este espessamento valor prognóstico bem demostrado como preditor de eventos vasculares futuros. O ultrassom em escala de cinza foi utilizado, até recentemente, como método não invasivo padrão para identificar e discriminar a composição da placa aterosclerótica. Uma abordagem inovadora da análise dos sinais de radiofrequência emitidos pelo ultrassom modo B, tornou possível o desenvolvimento de uma técnica ultrassonográfica em cores denominada caracterização tecidual ultrassonográfica (CATUS), esta é promissora na detecção de placas ateroscleróticas vulneráveis e na avaliação da sua história natural; logo, estudos prospectivos utilizando as análises fornecidas por esse instrumento podem corroborar na distinção de placas susceptíveis à ruptura e, como consequência auxiliar na prevenção de eventos cardiovasculares. Objetivo: Determinar a diferença da caracterização tecidual ultrassonográfica (CATUS) comparada à ultrassonografia modo B na hiperplasia miointimal. Hipótese: Existe diferença na caracterização tecidual ultrassonográfica comparada à ultrassonografia modo B na hiperplasia miointimal. Tipo de estudo: Estudo experimental, transversal e comparativo. Amostra: A amostra foi probabilística, por conveniência, em 10 aortas de coelhos albinos do gênero Oryctolagus cuniculus, pertencendo à raça Nova Zelândia. Variável: A diferença da caracterização tecidual ultrassonográfica (CATUS) comparada ao ultrassom modo B na hiperplasia miointimal.

No description available.

O conhecimento de que o exercício é benéfico na doença aterosclerótica é baseado principalmente em estudos epidemiológicos. O objetivo deste trabalho foi investigar se o treinamento físico preventivo ou terapêutico altera a evolução da placa aterosclerótica. Camundongos LDLr-/- com 16 semanas de vida foram separados em dois programas: preventivo e terapêutico. Animais do programa preventivo receberam dieta normal ou aterogênica por 14 semanas. O treinamento físico foi iniciado concomitantemente ao início da dieta. Animais do programa terapêutico receberam dieta normal ou aterogênica por 28 semanas. O treinamento físico foi iniciado após 14 semanas do início da dieta, com placas bem estabelecidas. O treinamento físico aeróbico moderado foi realizado em esteira rolante, por 60 min, 5 dias/sem, durante 14 semanas. Massa corporal, pressão arterial caudal e freqüência cardíaca foram registradas. Lipoproteínas plasmáticas foram separadas por FPLC e colesterol total foi dosado por métodos enzimáticos. Foram quantificados tamanho, conteúdo de gordura e de colágeno da placa por coloração de oil-red O e picro-sirius. Citocinas TNF-, IL-6 foram medidas por Elisa. MMP-9 plasmática foi medida por zimografia. Marcadores inflamatórios teciduais, MMP-9, CD40/CD40L e nitrotirosina, foram medidos na placa por imunohistoquímica. O treinamento físico não modificou o tamanho da placa, mas tornou a placa mais estável por aumentar o conteúdo de colágeno. O treinamento físico diminuiu o conteúdo de gordura da placa, os fatores de risco e o CD40 somente no programa preventivo. Nenhuma alteração foi notada nos marcadores inflamatórios circulantes e na expressão de MMP-9 e formação de nitrotirosina na placa aterosclerótica. / The knowledge that exercise exerts beneficial effects on atherosclerotic disease is mainly based on epidemiological studies. Our aim was to investigate the effect of preventive and therapeutic exercise programs on atherosclerotic plaque formation and development. Sixteen-week-old LDLr-/- mice were randomly divided into preventive and therapeutic programs. Preventive programs mice received normal or atherogenic diet for 14 weeks. Exercise training started at the same time of dieting. Therapeutic programs mice received normal or atherogenic diet for 28 weeks. Exercise training started after 14 weeks of dieting when atherosclerosis plaques were already established. Moderate intensity aerobic exercise training was performed on a motor treadmill for 60 min, 5 days/wk, during 14 weeks. Body mass, caudal blood pressure and heart rate were registered. Plasma lipoproteins were separated by FPLC and total cholesterol was determined by enzymatic methods. Cross sections of aortic root were stained with oil-red O for plaque size and fat content. Aorta longitudinal sections were stained with picro-sirius for collagen content. TNF- and IL-6 cytokines were measured by Elisa. Plasmatic MMP-9 was determined by zimography. Inflammatory tissue markers, MMP-9, CD40/CD40L and nitrotirosine, were measured by immunohistochemistry. We concluded that exercise training did not modify plaque size, but turned it into a more stable one by increasing its collagen content. Exercise training reduced plaque fat content, risk factors and plaque CD40 expression only in the preventive program. No difference in systemic inflammatory markers, and in plaque MMP-9 expression and nitrotirosine formation was noted.

Polyphenols are naturally-occurring phytochemicals, which form an integral part of the human diet. Results from epidemiological studies have associated polyphenol intake with reduced risk of cardiovascular diseases. Previous human intervention studies suggested that dietary polyphenols exert their cardioprotective effects through their antioxidant and anti-inflammatory effects. While most in vitro experiments have not accounted for the bioavailability and metabolism of these polyphenols, our work has provided direct evidence, using quercetin, that metabolic transformation, together with bioavailability, exert profound effects on bioactivity. We examined the effect of quercetin and its major metabolites on the production of pro-inflammatory eicosanoids by human leukocytes. Studies comparing free radical scavenging, antioxidant activity and eicosanoid production demonstrate that there are different structural requirements for antioxidant and anti-inflammatory activity. We also investigated the effect of metabolic transformation on flavonoid bioactivity by comparing the activity of quercetin and its major metabolites to inhibit inflammatory eicosanoid production from human leukocytes. Quercetin was a potent inhibitor of leukotriene B4 formation in leukocytes (IC50 ~ 2µM), and its activity was dependent on specific structural features, particularly the 2,3 double bond of the C ring. Functionalisation of the 3'-OH group with either methyl or sulfate reduced inhibitory activity up to 50% while a glucuronide substituent at the 3-OH effectively removed the leukotriene B4 inhibitory activity. The major quercetin metabolite quercetin-3'-O-sulfate retained considerable lipoxygenase inhibitory activity (IC50 ~ 7 µM) while quercetin-3-O-glucuronide maintained antioxidant activity but had no lipoxygenase inhibitory activity at physiologically relevant concentrations. We conclude that structural modification of quercetin due to metabolic transformation had a profound effect on bioactivity, and that the structural features required for antioxidant activity of 8 quercetin and related flavonoids were unrelated to those required for inhibition of inflammatory eicosanoids.

O conhecimento de que o exercício é benéfico na doença aterosclerótica é baseado principalmente em estudos epidemiológicos. O objetivo deste trabalho foi investigar se o treinamento físico preventivo ou terapêutico altera a evolução da placa aterosclerótica. Camundongos LDLr-/- com 16 semanas de vida foram separados em dois programas: preventivo e terapêutico. Animais do programa preventivo receberam dieta normal ou aterogênica por 14 semanas. O treinamento físico foi iniciado concomitantemente ao início da dieta. Animais do programa terapêutico receberam dieta normal ou aterogênica por 28 semanas. O treinamento físico foi iniciado após 14 semanas do início da dieta, com placas bem estabelecidas. O treinamento físico aeróbico moderado foi realizado em esteira rolante, por 60 min, 5 dias/sem, durante 14 semanas. Massa corporal, pressão arterial caudal e freqüência cardíaca foram registradas. Lipoproteínas plasmáticas foram separadas por FPLC e colesterol total foi dosado por métodos enzimáticos. Foram quantificados tamanho, conteúdo de gordura e de colágeno da placa por coloração de oil-red O e picro-sirius. Citocinas TNF-, IL-6 foram medidas por Elisa. MMP-9 plasmática foi medida por zimografia. Marcadores inflamatórios teciduais, MMP-9, CD40/CD40L e nitrotirosina, foram medidos na placa por imunohistoquímica. O treinamento físico não modificou o tamanho da placa, mas tornou a placa mais estável por aumentar o conteúdo de colágeno. O treinamento físico diminuiu o conteúdo de gordura da placa, os fatores de risco e o CD40 somente no programa preventivo. Nenhuma alteração foi notada nos marcadores inflamatórios circulantes e na expressão de MMP-9 e formação de nitrotirosina na placa aterosclerótica. / The knowledge that exercise exerts beneficial effects on atherosclerotic disease is mainly based on epidemiological studies. Our aim was to investigate the effect of preventive and therapeutic exercise programs on atherosclerotic plaque formation and development. Sixteen-week-old LDLr-/- mice were randomly divided into preventive and therapeutic programs. Preventive programs mice received normal or atherogenic diet for 14 weeks. Exercise training started at the same time of dieting. Therapeutic programs mice received normal or atherogenic diet for 28 weeks. Exercise training started after 14 weeks of dieting when atherosclerosis plaques were already established. Moderate intensity aerobic exercise training was performed on a motor treadmill for 60 min, 5 days/wk, during 14 weeks. Body mass, caudal blood pressure and heart rate were registered. Plasma lipoproteins were separated by FPLC and total cholesterol was determined by enzymatic methods. Cross sections of aortic root were stained with oil-red O for plaque size and fat content. Aorta longitudinal sections were stained with picro-sirius for collagen content. TNF- and IL-6 cytokines were measured by Elisa. Plasmatic MMP-9 was determined by zimography. Inflammatory tissue markers, MMP-9, CD40/CD40L and nitrotirosine, were measured by immunohistochemistry. We concluded that exercise training did not modify plaque size, but turned it into a more stable one by increasing its collagen content. Exercise training reduced plaque fat content, risk factors and plaque CD40 expression only in the preventive program. No difference in systemic inflammatory markers, and in plaque MMP-9 expression and nitrotirosine formation was noted.

Made available in DSpace on 2015-07-22T20:49:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-10-26. Added 1 bitstream(s) on 2015-08-11T03:26:12Z : No. of bitstreams: 1 Publico-12819.pdf: 1531638 bytes, checksum: 73bb6d6fd7336127fb68327a46db002f (MD5) / Introducao: Euterpe oleracea (acai) e uma fruta da regiao amazonica, cuja composicao quimica pode ser benefica para individuos com aterosclerose. Nos hipotetizamos que o consumo de Euterpe oleracea poderia reduzir o desenvolvimento da aterosclerose por uma reducao na absorcao e sintese de colesterol. Metodos: Coelhos machos Nova Zelandia foram alimentados com uma dieta enriquecida em colesterol (0.5%) por 12 semanas, quando foram aleatoriamente distribuidos para tratamento com Euterpe oleracea ou agua alem de dieta enriquecida em colesterol (0,05%) por 12 semanas adicionais. Fitosterois plasmaticos e desmosterol foram determinados por cromatografia liquida de alto desempenho e espectrometria de massa. As lesoes ateroscleroticas foram estimadas por planimetria computadorizada. Resultados: Ao sacrificio, os animais tratados com Euterpe oleracea tiveram menores niveis de colesterol total (p=0.03) e de colesterol nao-HDL (p=0.03) em comparacao aos controles. Estes animais tiveram menores areas de aterosclerose em suas aortas ((p=0.001) e menor relacao intima/media (p=0.002) em comparacao aos controles. Ao final do estudo, os valores plasmaticos de campesterol, ƒÀ-sitosterol, e desmosterol nao diferiram entre os grupos. Entretanto, os animais tratados com Euterpe oleracea mostraram menores valores para as relacoes desmosterol/campesterol (p=0.026) e desmosterol/ƒÀ-sitosterol (p=0.006) em comparacao aos controles. Conclusoes: Consumo do extrato de Euterpe oleracea marcadamente melhora o perfil lipidico e atenua a aterosclerose. Estes efeitos foram em parte relacionados a um melhor balanco entre sintese e absorcao de esterois. / Background: Euterpe oleracea (acai) is a fruit from the Amazon region, whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe oleracea would reduce therosclerosis development by a decrease in cholesterol absorption and synthesis. Methods: Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe oleracea extract or water plus a 0.05% cholesterol-enriched diet for additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry. Results: At sacrifice, animals treated with Euterpe oleracea had lower levels of total cholesterol (p=0.03) and non-HDL-cholesterol (p=0.03) as compared to controls. These animals had smaller atherosclerotic plaque area in their aortas (p=0.001) and a smaller intima/media ratio (p=0.002) in comparison with controls. At the end of the study, campesterol, ƒÀ-sitosterol, and desmosterol plasma levels did not differ between groups. However, animals treated with Euterpe oleracea showed lower values for the desmosterol/campesterol (p=0.026) and desmosterol/ƒÀ-sitosterol (p=0.006) ratios as compared to controls. Conclusion: Consumption of Euterpe oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols. / TEDE / BV UNIFESP: Teses e dissertações