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INTRODUCTION: Optimal vascular function is a hallmark of cardiovascular health. Specifically, the balance of vasoconstricting and vasodilating substances is recognized as a marker of vascular health. One of the greatest challenges to vascular health and vasodilatory balance is tumor necrosis factor alpha (TNFα)-mediated inflammation. Uncovering effective strategies that maintain a vascular environment that is more vasodilatory and antithrombotic in the face of an inflammatory challenge is favorable. PURPOSE: To test the ability of various antithrombotic and provasodilatory treatments, as well as combinations thereof, to prevent unfavorable changes in markers of endothelial dysfunction in human umbilical vein endothelial cells when presented with an inflammatory challenge. METHODS: Human umbilical vein endothelial cells were pretreated with exercise-like levels of laminar shear stress (LSS), aspirin, celecoxib, and their combination before a TNFα challenge. Western blot analysis as well as colorimetric assays were used to determine levels of endothelial nitric oxide synthase (eNOS) and prostacyclin (6-keto PGF1α)/thromboxane (TXB2) metabolite ratio, respectively. RESULTS: Neither aspirin nor celecoxib were effective in preventing TNFα-induced reduction in eNOS. Further, aspirin was unable to maintain baseline levels of prostacyclin/thromboxane ratio in the face of the inflammatory challenge. Laminar shear stress, aspirin/LSS combination, and celecoxib/LSS combination were all able to prevent TNFα-induced alterations in eNOS levels and prostacyclin/thromboxane ratio. CONCLUSIONS: Effective strategies to maintain a healthy endothelium, and therefore resistance vessel health, need to include exercise-levels of shear stress to be effective.

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As healthcare progresses toward individualized medicine, understanding how different racial groups respond to lifestyle interventions is valuable. It is established that African Americans have disproportionate levels of cardiovascular disease and impaired vascular health, and clinical practice guidelines suggest lifestyle interventions as the first line of treatment. Recently, the authors reported that 6 months of aerobic exercise improved inflammatory markers, flow-mediated dilation (FMD), and levels of circulating endothelial microparticles (EMPs) in African American adults. This study is a subgroup analysis of the aerobic exercise-induced changes in vascular health and blood pressure (BP) measures, including carotid artery intima-media thickness (IMT), nitroglycerin-mediated dilation (NMD), ambulatory BP, and office BP. Sedentary African American adults (53.4±6.2 years; 21 women and 5 men) showed improved vascular health but no change in BP. Carotid artery IMT decreased 6.4%, plasma nitric oxide levels increased 76.6%, plasma EMP levels decreased, percentage of FMD increased 59.6%, and FMD/NMD ratio increased 36.2% (P<.05 for all). Six months of aerobic exercise training is sufficient to elicit improvements in vascular structure and function in African Americans, even without improvements in BP measures or NMD (ie, smooth muscle function). To our knowledge, this is the first study to report such findings in African Americans.

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The polymorphisms of endothelial nitric oxide synthase (eNOS) are associated with reduced eNOS activity. Aerobic exercise training (AEX) may influence resting nitric oxide (NO) production, oxidative stress and blood pressure. The purpose of this study was to investigate the effect of AEX on the relationship among blood pressure, eNOS gene polymorphism and oxidative stress in pre-hypertensive older people. 118 pre-hypertensive subjects (59 ± 6 years) had blood samples collected after a 12 h overnight fast for assessing plasma NO metabolites (NOx) assays, thiobarbituric acid reactive substances (T-BARS) and superoxide dismutase activity (ecSOD). eNOS polymorphism (T-786C and G-894T) was done by standard PCR methods. All people were divided according to the genotype results (G1: TT/GG, G2: TT/GT + TT, G3: TC + CC/GG, G4: TC + CC/GT + TT). All parameters were measured before and after 6 months of AEX (70% of VO(2 max)). At baseline, no difference was found in systolic and diastolic blood pressure, ecSOD and T-BARS activity. Plasma NOx levels were significantly different between G1 (19 ± 1 µM) and G4 (14.2 ± 0.6 µM) and between G2 (20.1 ± 1.7 µM) and G4 (14.2 ± 0.6 µM). Therefore, reduced NOx concentration in G4 group occurred only when the polymorphisms were associated, suggesting that these results are more related to genetic factors than NO-scavenging effect. After AEX, the G4 increased NOx values (17.2 ± 1.2 µM) and decreased blood pressure. G1, G3 and G4 decreased T-BARS levels. These results suggest the AEX can modulate the NOx concentration, eNOS activity and the relationship among eNOS gene polymorphism, oxidative stress and blood pressure especially in C (T-786C) and T (G-894T) allele carriers.

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O óxido nítrico (NO) tem sido considerado como um dos importantes mecanismos para o controle da pressão arterial. Proveniente do metabolismo da L-arginina, a partir da ativação da “óxido nítrico sintase endotelial” (eNOS), o NO contribui para aumentar o grau de vasodilatação e, consequentemente, diminuição da pressão arterial. Mas, existem alguns mecanismos que podem contribuir para a diminuição das concentrações de NO, como por exemplo, o polimorfismo T-786C do gene da eNOS e a biodisponibilidade do NO. Várias substâncias atuam no sentido de neutralizar o efeito do NO, impedindo a vasodilatação. Contrapondo-se a esses efeitos, o exercício físico tem sido considerado uma importante ferramenta para o aumento das concentrações de NO. Este efeito ocorre, basicamente, pelo aumento do shear stress proveniente do próprio exercício físico, que possui a capacidade de estimular um aumento na expressão do gene da eNOS, combatendo a deficiência provocada pelo polimorfismo e, também, devido à capacidade de aumentar a produção de superóxido dismutase (SOD), enzima que tem a capacidade de reagir com as substâncias que estariam neutralizando o NO. Desta forma, o exercício físico pode ser considerado como um importante mecanismo para aumentar a produção e a biodisponibilidade do NO.

The generation of nitric oxide (NO) by the vascular endothelium maintains a vasodilator tone that is essential for the regulation of blood pressure. Low concentration of NO may contribute for the development of cardiovascular disease, especially hypertension. There are two mechanisms that can be involved in this decrease: (a) individuals with eNOS gene polymorphism have a significantly decreased promoter activity. This mutation suppresses eNOS transcription, which is consistent with reduced NO production, (b) Nitric oxide bioavailability that is crucial for maintaining vascular endothelial health and function. This mechanism depends on the process controlling synthesis and destruction of nitric oxide. Evidence supports a major contribution by oxidative stress-induced destruction of nitric oxide to the endothelial dysfunction that accompanies a number of cardiovascular disease states including hypertension. The superoxide dismutase (SOD) has been considering as a mechanism against the oxidative stress because it has the capacity to increase NO bioavailability. Since eNOS and SOD both contribute to the levels of bioactive nitric oxide (NO) and can be stimulated by shear stress, the exercise training assume an important function to increase NO concentration in the blood vessel. The capacity for exercise training to regulate vascular endothelial function, nitric oxide bioavailability, and oxidative stress is an example of how lifestyle can complement medicine and pharmacology in the prevention and management of hypertension.

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