Effect Of Red Wine Polyphenols Research Articles

Beneficial Effects of Red Wine Polyphenols on Human Health: Comprehensive Review.

Polyphenols are secondary plant metabolites synthesized during the development of the grape berry as a response to stress conditions. They are important constituents in red wines that contribute to the sensory properties and antioxidant activity of wines. Due to the development of highly sophisticated analytical devices, it is now possible to characterize the structure of highly polymerized polyphenols and obtain a full polyphenol profile of red wines. Red wine polyphenols include the ones present in grapes as well as new polyphenol products formed during the winemaking process. Among them, the most important groups and their representatives are flavanols (catechin), stilbenes (trans-resveratrol), flavonols (quercetin) and hydroxybenzoic acids (gallic acid). It is known that polyphenols exhibit beneficial effects on human health, such as anti-inflammatory, anticarcinogenic and cardio-protective effects. Many studies have been conducted on the health effects of red wine polyphenols in cancer chemopreventive activities, neuroprotective effects and impact on cardiovascular diseases, gut microbiota in humans, etc. This review will provide major scientific findings on the impact of red wine polyphenols on human health as well as a review of polyphenols present in red wines and their main features.

The evaluation of the antidiabetic effects of red wine polyphenols with the view of in silico prediction methods

Moderate red wine consumption has been shown to decrease the risk of cardiovascular diseases and beneficial effects on lipid metabolism and patients with type 2 diabetes mellitus (T2DM). Though there were studies on the antidiabetic effects of polyphenols, in this study we evaluated the red wine polyphenols holistically and analyzed by network pharmacology with the basis of multicomponent-multitarget paradigm. 116 compounds with a polyphenolic structure determined in red wine were listed in this study. Compounds were filtered due to their bioavailability scores and 43 compounds that met the selection criteria were further searched for their targets. The study was conducted by constructing three subgroups. These subgroups include i) all polyphenols (SG1), ii) all polyphenols except t-resveratrol (SG2), and iii) t-resveratrol (SG3). ‘Compound-Target’ network of SG1, SG2, and SG3 was merged with ‘Disease-Target' network. These common targets were subjected to DAVID database. The KEGG pathway enrichment analysis showed enrichment for FOXO signaling pathway, insulin resistance, TNF signaling pathway, PI3K-AKT signaling pathway, and HIF-1 signaling pathway that were related to T2DM. The key targets were defined as AKT1, STAT3, and IL6 using protein-protein interaction network. All 43 compounds were tested for their binding abilities to the key targets. Catechin gallate, (−)-epicatechin 3-O-gallate, rosmarinic acid, piceatannol 3′-O-glucoside, apigenin, ellagic acid, δ-viniferin, and t-resveratrol were found as prominent compounds in molecular docking studies. Our findings suggested that polyphenols in red wine could make improvements in glucose metabolism through FOXO and PI3K-AKT signaling pathway and could be protective against type 2 diabetes related complications.

Red wine polyphenols modulate bone loss in the ovariectomized rat model of postmenopausal osteoporosis

The aim of this study was to examine the effect of Red Wine Polyphenols (RWPs) extract on bone mineral density (BMD) in the ovariectomized (OVX) rat model. Thirty-five 10-month-old Wistar rats were separated into controls (CTRL), OVX and OVX plus RWPs in their drinking water (dose, 50 mg/kg body weight per day), starting immediately after OVX for 6 months. Βody and uterine weight, BMD of the tibia at baseline, 3 and 6 months post-OVX, and 3-pointing bending of the femur, were examined. Statistical comparison of the total tibia BMD within groups during the study period showed a significant reduction in the OVX and OVX+RWPs groups both from baseline to 3 and 6 months and from 3 to 6 months, whereas in the CTRL group, there was no significant change. For the proximal tibial metaphysis, comparison of BMD percentage changes from baseline to 3 months and 6 months and from 3 to 6 months revealed highly statistical differences between OVX and OVX+RWPs groups (P = 0.000). OVX induced a significant reduction of biomechanical parameters as expected; the 3-point bending test showed that the maximum force before fracture, energy absorption and fracture stress significantly increased in the OVX group treated with RWPs compared with the nontreated OVX rats (P = 0.048, P = 0.002 and P = 0.003, respectively). Dietary intake of RWPs for 6 months significantly prevented trabecular bone loss and improved bone strength in estrogen-deficient ovariectomized rats.

Proteomic analysis of Saccharomyces cerevisiae to study the effects of red wine polyphenols on oxidative stress.

Understanding the molecular mechanisms underlying the "French paradox" has contributed to a growing interest in the investigation of the biological activity of red wine polyphenols (RWP). The main goal of this research is to provide valuable information on how RWP could exert their biological action at the cellular level. So, we report a proteomic analysis of S. cerevisiae exposed to both pro-oxidant (H2O2) and antioxidant (wine) agents. Cellular proteome analysis shows that RWP modify the level of certain proteins. Under both normal conditions (Wine treatment) and oxidative stress situations (Wine + H2O2 treatment), the proteins involved in the metabolism and biosynthesis of biomolecules were down-regulated, while one ribosomal protein was up-regulated, probably performing its ribosome-independent functions, and so contributing to the stress defense system. Considering this action mechanism, we suggest that RWP may be acting as mild pro-oxidants and, therefore, exerting a hormetic effect that leads to the strengthening of cells' antioxidant capacity.

Polyphenol Extracts from Red Wine and Grapevine: Potential Effects on Cancers.

Wine has been popular worldwide for many centuries and currently remains an important component of our diet. Scientific interest in wine and its health effects has grown considerably since the 1990s with the emergence of the “French Paradox” concept, correlating moderate wine consumption, a characteristic of the Mediterranean diet, and low incidence of coronary heart diseases. Since then, the positive effects on health, health promotion, disease prevention, and disease prognosis of moderate wine consumption, in particular red wine, have been attributed to its polyphenolic compounds such as resveratrol, quercetin, and other flavonoids acting as antioxidants. Several epidemiological, in vivo and in vitro, studies have reported that moderate red wine or red wine polyphenolic extract consumption may be active in the prevention and treatment of chronic diseases such as cardiovascular disease, metabolic syndrome, degenerative pathologies, and cancer. The aim of this review is to summarize the current findings about the effects of red wine polyphenols on cancer and to discuss how the polyphenolic composition of red wine may influence its chemopreventive properties.

Estrogen Receptor α Participates to the Beneficial Effect of Red Wine Polyphenols in a Mouse Model of Obesity-Related Disorders.

Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders associated with obesity. Previously, we demonstrated that the alpha isoform of estrogen receptor (ERα) triggers the vascular protection of polyphenols. Here, we investigated the contribution of ERα on the effects of polyphenols on cardiovascular and metabolic alterations associated with obesity. We used ovariectomized wild type or ERα-deficient mice receiving standard (SD) or western (WD) diets, or SD and WD containing polyphenols (SD+polyphenols and WD+polyphenols, respectively) over a 12-week period. Body weight was measured during treatment. Echocardiography examination was performed before sacrifice. Blood and tissues were sampled for biochemical and functional analysis with respect to nitric oxide (NO•) and oxidative stress. Vascular reactivity and liver mitochondrial complexes were analyzed. In WD-fed mice, polyphenols reduced adiposity, plasma triglycerides and oxidative stress in aorta, heart, adipose and liver tissues and enhanced NO• production in aorta and liver. ERα deletion prevented or reduced the beneficial effects of polyphenols, especially visceral adiposity, aortic and liver oxidative stresses and NO• bioavailability. ERα deletion, however, had no effect on polyphenol’s ability to decrease the fat accumulation and oxidative stress of subcutaneous adipose tissue. Also, ERα deletion did not modify the decrease of ROS levels induced by polyphenols treatment in the visceral adipose tissue and heart from WD-fed mice. Dietary supplementation of polyphenols remarkably attenuates features of metabolic syndrome; these effects are partially mediated by ERα-dependent mechanisms. This study demonstrates the therapeutic potential of this extract in metabolic and cardiovascular alterations linked to excessive energy intake.

Effect of Red Wine Polyphenols on the Expression of Transthyretin in Murine Choroid Plexus.

Plasmatic transthyretin may be regarded as a suitable candidate biomarker for the onset, severity, and progression of Alzheimer disease. The aim of the present experimental work was to evaluate the effect of red wine polyphenols (RWPs) on the expression of transthyretin in murine choroid plexus. In contrast to what generally reported in literature for polyphenols, our experimental results indicated a correlation between RWPs assumption and a decrease of transthyretin expression, with a non-dose dependent trend. The present study would point out the attention on the possible pro-oxidant effects of red wine polyphenols at certain doses, although further in vitro, in vivo, and clinical experiments must be performed in order to clarify the mechanisms of action at the base of observed results.

Putative Role of Red Wine Polyphenols against Brain Pathology in Alzheimer's and Parkinson's Disease.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common age-related neurodegenerative disorders and hence pose remarkable socio-economical burdens to both families and state. Although AD and PD have different clinical and neuropathological features, they share common molecular mechanisms that appear to be triggered by multi-factorial events, such as protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation, ultimately leading to neuronal cell death. Currently, there are no established and validated disease-modifying strategies for either AD or PD. Among the various lifestyle factors that may prevent or slow age-related neurodegenerative diseases, epidemiological studies on moderate consumption of red wine, especially as part of a holistic Mediterranean diet, have attracted increasing interest. Red wine is particularly rich in specific polyphenolic compounds that appear to affect the biological processes of AD and PD, such as quercetin, myricetin, catechins, tannins, anthocyanidins, resveratrol, and ferulic acid. Indeed, there is now a consistent body of in vitro and in vivo data on the neuroprotective effects of red wine polyphenols (RWP) showing that they do not merely possess antioxidant properties, but may additionally act upon, in a multi-target manner, the underlying key mechanisms featuring in both AD and PD. Furthermore, it is important that bioavailability issues are addressed in order for neuroprotection to be relevant in a clinical study scenario. This review summarizes the current knowledge about the major classes of RWP and places into perspective their potential to be considered as nutraceuticals to target neuropathology in AD and PD.

Role of Arginases in the Angiotensin II-Induced Hypertension-Associated Endothelial Dysfunction in the Rat Aorta

Increases in arginase activity have been reported in a variety of diseases associated with vascular dysfunction. As arginases compete with NO synthase for their common substrate L-arginine, an increased arginase activity might decrease the bioavailability of nitric oxide (NO), a major vasoprotective factor. Moreover, red wine polyphenols (RWPs) have been shown to prevent the endothelial dysfunction in several rat models, at least in part, through protection of NO bioavailability. The aim of the present study was to determine whether an increased arginase activity contributes to the Ang II-induced hypertension-associated endothelial dysfunction in the rat aorta, and, if so, to determine the protective effect of RWPs. Rats received either RWPs (150 mg/kg/day) or apocynin, an antioxidant and an inhibitor of NADPH oxidase (100 mg/kg/day), in the drinking water for 7 days before the infusion of Ang II (0.4 mg/kg/day) for 14 days. Arterial pressure was measured in conscious rats. After euthanasia, vascular reactivity was assessed in organ chambers, arginases activity by a colorimetric assay, and expression level of arginases by immunofluorescence. Ang II-induced hypertension is associated with an endothelial dysfunction characterized by a reduced relaxation and an increased contraction in response to acetylcholine. Moreover, Ang II infusion increased both expression and activity of arginases. Treatment with RWPs and apocynin prevented the Ang II-induced hypertension and endothelial dysfunction, and the associated increased arginase expression and activity. Altogether, these findings suggest that Ang II-induced hypertension and endothelial dysfunction are associated with an increased expression and activity of vascular arginases, which can be prevented by RWPs and apocynin. These results constitute a real contribution in the understanding of the physiopathology of endothelial dysfunction arterial high blood pressure induced by the angioyensine II. Besides, they offer real perspectives in prevention treatment of these cardiovascular disorders.

ENOS Promoter Activation by Red Wine Polyphenols: an Interaction Study

Beneficial effects of red wine polyphenols on cardiovascular health are well known. The aim of our research was an interaction study of four red wine polyphenols – resveratrol (R), quercetin (Q), kaempferol (KF) and isorhamnetin (IR) of their ability to activate endothelial NO synthase (eNOS) promoter when used alone and in equimolar mixtures. To determine their activity, we performed a luciferase reporter gene assay on EA.hy926 cells stably transfected with a luciferase reporter gene construct containing eNOS promoter. The Bradford assay was also performed to account the cytotoxicity and/or the cell number differences. The median effect equation, as an interaction analysis evaluating synergy or antagonism of the combinations was done according to mass-action law principle. Isobolographic method was performed on selected double mixtures and dose reduction index was calculated for all mixtures. All single polyphenols activated eNOS promoter. The EC50 values were in micromolar concentrations ranging from 3.44 μM (R2 = 0.96) for kaempferol to 9.89 μM for isorhamnetin (R2 = 0.94). All mixtures activated eNOS promoter, but their interactions varied from synergy (Q+R, Q+IR+KF, Q+R+KF and Q+R+IR+KF), through additive (R+IR+KF) to antagonistic interaction (R+IR, R+KF, Q+IR, Q+KF, IR+KF and R+Q+IR). In this study, we show for the first time that red wine polyphenols activated eNOS promoter when used alone and in mixtures with different type of interactions.

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD

In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.

Grape-Derived Polyphenols Prevent Doxorubicin-Induced Blunted EDH-Mediated Relaxations in the Rat Mesenteric Artery: Role of ROS and Angiotensin II

This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO) and endothelium-derived hyperpolarization (EDH) in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs), a rich natural source of antioxidants. Male Wistar rats were assigned into 4 groups: control, RWPs, doxorubicin, and doxorubicin + RWPs. Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS) using dihydroethidine and the expression levels of small and intermediate conductance calcium-activated potassium channels (SKCa, IKCa) and connexin 40 (Cx40), which are involved in EDH-type relaxations, endothelial NO synthase (eNOS), angiotensin II, and AT1 receptors by immunofluorescence. The doxorubicin treatment impaired EDH-mediated relaxations, whereas those mediated by NO were minimally affected. This effect was associated with reduced expression levels of SKCa, IKCa, and Cx40, increased expression levels of eNOS, angiotensin II, and AT1 receptors, and formation of ROS in mesenteric arteries. RWPs prevented both the doxorubicin-induced blunted EDH-type relaxations and the increased vascular oxidative stress, and they improved the expression levels of target proteins. These findings suggest that polyphenol-rich natural products might be of interest in the management of doxorubicin-induced vascular injury possibly by improving the vascular angiotensin system.

Dealcoholized Red Wine Decreases Systolic and Diastolic Blood Pressure and Increases Plasma Nitric Oxide

Rationale: Experimental studies have shown a potential blood pressure (BP) lowering effect of red wine polyphenols, whereas the effects of ethanol and polyphenols on BP in humans are not yet clear. Objective: The aim of the present work was to evaluate the effects of red wine fractions (alcoholic and nonalcoholic) on BP and plasma nitric oxide (NO) in subjects at high cardiovascular risk. Methods and Results: Sixty-seven men at high cardiovascular risk were studied. After a 2-week run-in period, subjects were randomized into 3 treatment periods in a crossover clinical trial, with a common background diet plus red wine (30g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30g alcohol/day), lasting 4 weeks each intervention. At baseline and after each intervention, anthropometrical parameters, BP and plasma NO were measured. Systolic and diastolic BP decreased significantly after the dealcoholized red wine intervention and these changes correlated with increases in plasma NO. Conclusions: Dealcoholized red wine decreases systolic and diastolic BP. Our results point out through an NO-mediated mechanism. The daily consumption of dealcoholized red wine could be useful for the prevention of low to moderate hypertension. Trial registered at controlled-trials.com : ISRCTN88720134.

Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: A randomized clinical trial

Epidemiological data suggest that moderate red wine consumption reduces cardiovascular mortality and the incidence of diabetes. However, whether these effects are due to ethanol or to non-alcoholic components of red wine still remains unknown. The aim of the present study was to compare the effects of moderate consumption of red wine, dealcoholized red wine, and gin on glucose metabolism and the lipid profile. Sixty-seven men at high cardiovascular risk were randomized in a crossover trial. After a run-in period, all received each of red wine (30g alcohol/d), the equivalent amount of dealcoholized red wine, and gin (30g alcohol/d) for 4 week periods, in a randomized order. Fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), plasma lipoproteins, apolipoproteins and adipokines were determined at baseline and after each intervention. Fasting glucose remained constant throughout the study, while mean adjusted plasma insulin and HOMA-IR decreased after red wine and dealcoholized red wine. HDL cholesterol, Apolipoprotein A-I and A-II increased after red wine and gin. Lipoprotein(a) decreased after the red wine intervention. These results support a beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, conferring greater protective effects on cardiovascular disease to red wine than other alcoholic beverages. www.isrctn.org: ISRCTN88720134.

Increased Microparticle Production and Impaired Microvascular Endothelial Function in Aldosterone-Salt-Treated Rats: Protective Effects of Polyphenols

We aimed to characterize circulating microparticles in association with arterial stiffness, inflammation and endothelial dysfunction in aldosterone-salt-induced hypertension in rats and to investigate the preventive effects of red wine polyphenols. Uninephrectomized male Sprague-Dawley rats were treated with aldosterone-salt (1 µg.h−1), with or without administration of either red wine polyphenols, Provinols™ (20 mg.kg−1.day−1), or spironolactone (30 mg.kg−1.day−1) for 4 weeks. Microparticles, arterial stiffness, nitric oxide (NO) spin trapping, and mesenteric arterial function were measured. Aldosterone-salt rats showed increased microparticle levels, including those originating from platelets, endothelium and erythrocytes. Hypertension resulted in enhanced aortic stiffness accompanied by increased circulating and aortic NO levels and an upregulation of aortic inducible NO-synthase, NFκB, superoxide anions and nitrotyrosine. Flow-induced dilatation was reduced in mesenteric arteries. These effects were prevented by spironolactone. Provinols™ did not reduce arterial stiffness or systolic hypertension but had effects similar to those of spironolactone on endothelial function assessed by flow-mediated vasodilatation, microparticle generation, aortic NO levels and oxidative stress and apoptosis in the vessel wall. Neither the contractile response nor endothelium-dependent relaxation in mesenteric arteries differed between groups. The in vivo effects of Provinols™ were not mediated by mineralocorticoid receptors or changes in shear stress. In conclusion, vascular remodelling and endothelial dysfunction in aldosterone-salt-mediated hypertension are associated with increased circulating microparticles. Polyphenols prevent the enhanced release of microparticles, macrovascular inflammation and oxidative stress, and microvascular endothelial dysfunction independently of blood pressure, shear stress and mineralocorticoid receptor activation in a model of hyperaldosteronism.

Red wine polyphenols do not lower peripheral or central blood pressure in high normal blood pressure and hypertension

Epidemiological data suggest that modest red wine consumption may reduce cardiovascular disease risk. Red wine polyphenols improved human endothelial vascular function and reduced blood pressure (BP) in animal studies, but the results of human intervention studies investigating the effect of red wine polyphenols on BP are inconsistent. The objective was to investigate whether polyphenols extracted from red wine reduce peripheral and central BP in subjects with high-normal BP or grade 1 hypertension. In a double-blind, placebo-controlled three-period crossover trial, we assigned 61 subjects (mean age 61.4 ± 8.4 years) with office systolic BP 135 ± 9 mm Hg and diastolic BP 82 ± 8 mm Hg to dairy drinks containing either placebo, 280 mg red wine polyphenols, or 560 mg red wine polyphenols. After each 4-week intervention period, office and 24-h ambulatory BP measurements, and central hemodynamic measurements derived from continuous finger BP recordings were assessed. Polyphenol treatment did not significantly affect 24-h BP: systolic/diastolic BP was 143 ± 2/84 ± 1 mm Hg after placebo, 143 ± 2/84 ± 1 mm Hg after 280 mg/day of red wine polyphenols, and 142 ± 2/83 ± 1 mm Hg after 560 mg/day. Neither dose of polyphenol treatment changed office or central BP, aortic augmentation index (AIx) or pulse wave reflection index. Intake of red wine polyphenols in two different dosages for 4 weeks did not decrease peripheral or central BP in subjects with a high normal or grade 1 hypertension. Our findings do not support the hypothesis that polyphenols account for the suggested cardiovascular benefits of red wine consumption by lowering BP.

Red wine polyphenols protect n−3 more than n−6 polyunsaturated fatty acid from lipid peroxidation

Moderate red wine consumption is associated with decreased risk for cardiovascular disease; however, the underlying mechanisms are not completely understood. The main aim of this study was to investigate the effects of red wine polyphenols (WP) on the oxidizability of human plasma fatty acids, in particular those most involved in the inflammatory response — archidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The oxidizability of the major fatty acids of plasma was determined by measuring their loss gaschromatographycally during peroxidation kinetics induced by 2′-azobis(2-methylpropionamidine)-dihydrochloride. The capacity of WP to scavenge 1,1,diphenyl-2-picryl-hydrazyl (DPPH), superoxide anion and hydroxyl radicals, and trap total peroxyl radicals in plasma (TRAP) was also measured. WP (1.75–5 μg/mL) inhibited DPPH, superoxide anion and hydroxyl radicals and increased TRAP in a dose-dependent manner. WP (1.75 μg/mL) significantly protected all plasma PUFA from peroxidation but the protection of EPA and DHA was higher than that of AA. These results suggest that the association of WP to apolipoproteins makes EPA and DHA less accessible to hydro-soluble radicals than AA, thus providing a biochemical rationale for future ‘in vivo’ studies on the benefits to health of moderate red wine consumption.

Red wine polyphenols correct vascular function injured by chronic carbon tetrachloride intoxication

The aim of the study was to evaluate the effect of red wine polyphenols extract Provinols™ on the development of cardiovascular injury in the model of carbon tetrachloride (CCl4) intoxication. We followed the thoracic aorta vasoactivity and left ventricle nitric oxide (NO) synthase activity in male Wistar rats. In the preventive experiment lasting for 12 weeks the control group, the group receiving CCl4 (0.5 ml/kg) two times a week subcutaneously, the group receiving Provinols™ (30 mg/kg/day) in drinking water and the group receiving CCl4+Provinols™ was used. In the recovery experiment, the initial 12 weeks of CCl4 treatment were followed by 3 weeks of spontaneous recovery or recovery with Provinols™. CCl4-intoxication resulted in the injury of vasoactivity which was demonstrated by the inhibition of acetylcholine-induced relaxation as well as noradrenaline-induced contraction. In the preventive as well as recovery experiment administration of polyphenols refreshed endothelium-dependent relaxant response and normalized inhibited contraction to adrenergic stimuli. Provinols™ treatment significantly increased NO-synthase activity in all groups. The results revealed beneficial effects of red wine polyphenols on vascular function injured by chronic CCl4 intoxication. The correction of endothelial function seems to be attributed to the activation of NO pathway by polyphenols.

Endothelium-derived contracting factors mediate the Ang II-induced endothelial dysfunction in the rat aorta: preventive effect of red wine polyphenols

Angiotensin II (Ang II)-induced hypertension is associated with vascular oxidative stress and an endothelial dysfunction. This study examined the role of reactive oxygen species (ROS) and endothelium-derived contracting factors in Ang II-induced endothelial dysfunction and whether these effects are prevented by red wine polyphenols (RWPs), a rich source of natural antioxidants. Rats were infused with Ang II for 14 days. RWPs were administered in the drinking water 1 week before and during the Ang II infusion. Arterial pressure was measured in conscious rats. Vascular reactivity was assessed in organ chambers and cyclooxygenase-1 (COX-1) and COX-2 expression by Western blot and immunofluorescence analyses. Ang II-induced hypertension was associated with blunted endothelium-dependent relaxations and induction of endothelium-dependent contractions in the presence of nitro-L-arginine in response to acetylcholine (Ach). These effects were not affected by the combination of membrane permeant analogs of superoxide dismutase and catalase but were abolished by the thromboxane A(2) (TP) receptor antagonist GR32191B and the COX-2 inhibitor NS-398. The COX-1 inhibitor SC-560 also prevented contractile responses to Ach. Ang II increased the expression of COX-1 and COX-2 in the aortic wall. RWPs prevented Ang II-induced hypertension, endothelial dysfunction, and upregulation of COX-1 and COX-2. Thus, Ang II-induced endothelial dysfunction cannot be explained by an acute formation of ROS reducing the bioavailability of nitric oxide but rather by COX-dependent formation of contracting factors acting on TP receptors. RWPs are able to prevent the Ang II-induced endothelial dysfunction mostly due to their antioxidant properties.

Role of gender and estrogen receptors in the rat aorta endothelium-dependent relaxation to red wine polyphenols

Regular intake of moderate amounts of beverages rich in polyphenols such as red wine is associated with a protective effect on the vascular system, in part, by increasing the endothelial formation of nitric oxide (NO), a major vasoprotective factor. Since estrogens are potent inducers of NO formation and polyphenols have been shown to have phytoestrogen properties, we determined whether estrogen receptors mediate the stimulatory effect of red wine polyphenols (RWPs) on the endothelial formation of NO using isolated rat aortic rings and cultured endothelial cells. RWPs caused endothelium-dependent relaxations, which were more pronounced in the aorta of female than male rats. Increased relaxations were also observed to acetylcholine but not to sodium nitroprusside. Relaxations to RWPs were abolished by nitro l-arginine and MnTMPyP, markedly reduced by polyethyleneglycol-catalase and wortmannin, and not affected by the estrogen antagonist ICI 182,780 in aortic rings from males and females. eNOS expression was higher in aortic sections of female than male rats. RWPs caused the phosphorylation of Akt and eNOS in endothelial cells, which was unaffected by ICI 182,780. Thus, RWPs cause redox-sensitive PI3-kinase/Akt-dependent NO-mediated relaxations, which are more pronounced in the aorta of female than male rats; an effect most likely due to the increased expression level of eNOS rather than activation of estrogen receptors.