Dietary supplementation with concentrated RGJ improves the lipoprotein profile, reduces plasma concentrations of inflammatory biomarkers and oxidized LDL, and may favor a reduction in cardiovascular disease risk.

Background: Atherosclerotic cardiovascular disease is the most common cause of death among hemodialysis patients; it has been attributed to increased oxidative stress, dyslipidemia, malnutrition, and chronic inflammation. Activation of neutrophils is a wellrecognized feature in dialysis patients, and superoxide-anion production by neutrophil NADPH oxidase may contribute significantly to oxidative stress. Objective: The aim of the study was to compare the effects of dietary supplementation with concentrated red grape juice (RGJ), a source of polyphenols, and vitamin E on neutrophil NADPH oxidase activity and other cardiovascular risk factors in hemodialysis patients. Design: Thirty-two patients undergoing hemodialysis were recruited and randomly assigned to groups to receive dietary supplementation with RGJ, vitamin E, or both or a control condition without supplementation or placebo. Blood was obtained at baseline and on days 7 and 14 of treatment. Results: RGJ consumption but not vitamin E consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL cholesterol. Both RGJ and vitamin E reduced plasma concentrations of oxidized LDL and ex vivo neutrophil NADPH oxidase activity. These effects were intensified when the supplements were used in combination; in that case, reductions in the inflammatory biomarkers intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 also were observed. Conclusions: Regular ingestion of concentrated RGJ by hemodialysis patients reduces neutrophil NADPH-oxidase activity and plasma concentrations of oxidized LDL and inflammatory biomarkers to a greater extent than does that of vitamin E. This effect of RGJ consumption may favor a reduction in cardiovascular risk.

Red grape juice (RGJ) polyphenols have been shown to reduce circulating levels of LDL cholesterol and to increase LDL receptor activity. To explore the effect of RGJ-derived polyphenols on intracellular cholesterol homeostasis, human hepatocarcinoma HepG2 and promyelocytic HL-60 cell lines were incubated in serum-free medium, with or without LDL, in the presence or absence of RGJ. In the presence of LDL, RGJ increased both the activity and cell surface expression of the LDL receptor, and increased the cell total cholesterol content. In cells exposed to LDL, RGJ also increased levels of the active form of sterol regulatory element-binding protein-1 and mRNA expression of the LDL receptor and hydroxymethylglutaryl-CoA reductase. In contrast, RGJ caused a marked reduction in the expression of CYP7A1, apolipoprotein B, ABCA1, and ABCG5. Experiments using the acyl-CoA cholesterol acyltransferase inhibitor S-58035 indicated that no measurable free cholesterol from endocytosed LDL reaches the endoplasmic reticulum in cells treated with RGJ. Finally, fluorescence microscopy revealed that in RGJ-treated cells, DiI-labeled LDL did not colocalize with CD63, a protein localized at steady state in the internal vesicles of late endosomes. These results indicate that RGJ polyphenols disrupt or delay LDL trafficking through the endocytic pathway, thus preventing LDL cholesterol from exerting regulatory effects on intracellular lipid homeostasis.