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Background: Although oxidative stress plays a major role in endothelial dysfunction (ED), the role of glutathione (GSH), of nuclear erythroid-related factor 2 (Nrf2) and of related antioxidant genes (ARE) are yet unknown. In this study we combined an in vivo with an in vitro model to assess whether cigarette smoking affects flow-mediated vasodilation (FMD), GSH concentrations and the Nrf2/ARE pathway in human umbilical vein endothelial cells (HUVECs). Methods and Results: 52 healthy subjects (26 non-smokers and 26 heavy smokers) were enrolled in this study. In smokers we demonstrated increased oxidative stress, i.e., reduced concentrations of GSH and increased concentrations of oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in serum and in peripheral blood mononuclear cells (PBMC), used as in vivo surrogates of endothelial cells. Moreover we showed impairment of FMD in smokers and a positive correlation with the concentration of GSH in PBMC of all subjects. In HUVECs exposed to smokers' serum but not to non-smokers' serum we found that oxidative stress increased, whereas nitric oxide and GSH concentrations decreased; interestingly the expression of Nrf2, of heme oxygenase-1 (HO-1) and of glutamatecysteine ligase catalytic (GCLC) subunit, the rate-limiting step of synthesis of GSH, was decreased. To test the hypothesis that the increased oxidative stress in smokers may have a causal role in the repression of Nrf2/ARE pathway, we exposed HUVECs to increasing concentrations of oxPAPC and found that at the highest concentration (similar to that found in smokers' serum) the expression of Nrf2/ARE pathway was reduced. The knockdown of Nrf2 was associated to a significant reduction of HO-1 and GCLC expression induced by oxPAPC in ECs. Conclusions: In young smokers with ED a novel further consequence of increased oxidative stress is a repression of Nrf2/ ARE pathway leading to GSH depletion. [ABSTRACT FROM AUTHOR]

Background This study was conducted to evaluate (i) the effect of nebivolol, a selective β1-adrenergic receptor antagonist, on plasma concentration of asymmetric dimethylarginine (ADMA) and on flowmediated dilation (FMD) in essential hypertensive patients; (ii) the effect of serum derived from the treated hypertensive patients on ADMA and on dimethylarginine dimethylaminohydrolase 2 (DDAH2), the enzyme that selectively degrades ADMA, in human umbilical vein endothelial cells (HUVECs). Methods Forty healthy subjects and 40 matched essential hypertensive patients treated with atenolol and nebivolol according to a doubleblind, randomized design participated in the study. Evaluation of brachial artery (BA) reactivity was performed by a longitudinal B-mode scan of the right BA. ADMA and L-arginine were measured by high-performance liquid chromatography. DDAH2 expression and endothelial nitric oxide synthase activity (eNOS) were also evaluated in HUVECs. Results ADMA levels were significantly decreased and FMD increased only in patients receiving nebivolol (P < 0.01). Furthermore, in nebivolol group, we found a significant correlation between changes in ADMA levels and changes in FMD (P < 0.01). Sera derived from patients treated with nebivolol but not with atenolol decreased ADMA and increased DDAH2 expression and eNOS activity (P < 0.001) in HUVECs. Conclusions The results of this study demonstrate that the improvement of endothelial dysfunction induced by nebivolol in hypertensive patients may be related to its effect on circulating ADMA levels. Although the mechanism by which nebivolol reduces circulating ADMA in hypertensive patients remains unclear, our ex vivo results suggest that the upregulation of DDAH2 expression may have a role. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to investigate the effect of circulating levels of oxidized low-density lipoprotein (ox-LDL) on nuclear factor-kappa B (NF-kB) activation in peripheral blood mononuclear cells (PBMC) of patients with unstable angina (UA) or stable angina (SA) and control subjects. Background: Nuclear factor-kB might be involved in atherosclerosis, as is suggested by the presence of activated NF-kB in human atherosclerotic lesions. Methods: Levels of plasma ox-LDL and circulating NF-kB in PBMC (and in separated lymphocytes and monocytes) were measured in 27 control subjects and 29 SA and 27 UA patients. In in vitro studies, the effect of ox-LDL and of the sera derived from a subgroup of UA patients and control subjects on monocytic NF-kB activation was also evaluated. Results: The UA and SA patients had higher levels of circulating ox-LDL and NF-kB in PBMC than control subjects (p &#60; 0.001). The increase in circulating NF-kB was mainly due to the activation of monocytes. In the in vitro studies, ox-LDL dose-dependently increased the activation of NF-kB in monocytes, but not in lymphocytes derived from healthy volunteers. This increase was related to the expression of lectin-like ox-LDL receptor-1 on monocytes. The incubation of monocytes with the sera derived from the UA patients induced a significant increase in NF-kB activation compared with the sera derived from the control subjects. Conclusions: The data suggest that the activation of NF-kB in monocytes of UA patients is, at least in part, induced by circulating molecules such as ox-LDL, which has been found to be particularly elevated in UA patients. [Copyright &y& Elsevier]

We evaluated the effect of a low-fat, high carbohydrate (LFHC) diet on plasma lipids in 10 patients affected by familial endogenous hypertriglyceridemia. All the patients studied underwent a base-line period of 4 wk, a 12-wk intervention period, and an 8-wk switch-back period. During the control periods patients consumed ~145% of energy as fat and ~40% as carbohydrate. During the intervention period they consumed an isocaloric diet containing ~25% ofenergy as fat and ~60% as carbohydrate. Total plasma triglyceride and cholesterol levels decreased significantly after 45 and 90 d of treatment (p < 0.01). The reduction of plasma cholesterol was associated mostly with the decrease in VLDL cholesterol (p < 0.01) while LDL cholesterol increased at days 45 and 90 of the LFHC diet (p < 0.01). Finally, we observed a significant increase in HDL cholesterol both at days 45 and 90 of the LFHC diet (p < 0.01). The LFHC diet we used may be an useful tool in the management of hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

In examining a group of 90 hypercalcaemic patients (37 with primary hyperparathyroidism), a comparison was made of the diagnostic reliability of: 1) tests commonly used for diagnosis of primary hyperparathyroidism; 2) radioimmunoassay of plasma parathormone; 3) a recently introduced model of multivariate statistical analysis. The results indicate that, at present, the model of multivariate statistical analysis used is of higher diagnostic reliability in the diagnosis of primary hyperparathyroidism than renal phosphate excretion tests and the radioimmunoassay of PTH itself. [ABSTRACT FROM AUTHOR]