Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.     

Endothelial function and cardiovascular disease: Effects of quercetin and wine polyphenols

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.     

Estrogen and mitochondria: a new paradigm for vascular protection?

Mitochondrial dysfunction has been implicated as a cause of age-related disorders, and the mitochondrial theory of aging links aging, exercise, and diet. Endothelial dysfunction is a key paradigm for vascular disease and aging, and there is considerable evidence that exercise and dietary restriction protect against cardiovascular disease. Recent studies demonstrate that estrogen receptors are present in mitochondria and that estrogen promotes mitochondrial efficiency and decreases oxidative stress in the cerebral vasculature. Chronic estrogen treatment increases mitochondrial capacity for oxidative phosphorylation while decreasing production of reactive oxygen species. The effectiveness of estrogen against age-related cardiovascular disorders, including stroke, may thus arise in part from hormonal effects on mitochondrial function. Estrogen-mediated mitochondrial efficiency may also be a contributing factor to the longer lifespan of women.     

The role of virgin olive oil components in the modulation of endothelial function

The endothelium is involved in many of the processes related to the development of atherosclerosis, which is considered an inflammatory disease. Actually, traditional risk factors for atherosclerosis predispose to endothelial dysfunction, which is manifested as an increase in the expression of specific cytokines and adhesion molecules. There are firm evidence supporting the beneficial effects of olive oil, the most genuine component of the Mediterranean diet. Although the effects of olive oil and other oleic acid-rich dietary oils on atherosclerosis and plasma lipids are well known, the roles of minor components have been less investigated. Minor components constitute only 1-2% of virgin olive oil (VOO) and are composed of hydrocarbons, polyphenols, tocopherols, sterols, triterpenoids and other components usually found in traces. Despite their low concentration, non-fatty acid constituents may be of importance because studies comparing monounsaturated dietary oils have reported different effects on cardiovascular disease. Most of these compounds have demonstrated antioxidant, anti-inflammatory and hypolipidemic properties. In this review, we summarize current knowledge on the effects of these compounds contained in VOO on vascular dysfunction and the mechanisms by which they modulate endothelial activity. Such mechanisms involve the release of nitric oxide, eicosanoids (prostaglandins and leukotrienes) and adhesion molecules, in most cases by activation of nuclear factor kappaB by reactive oxygen species.     

Clinical aspects of reactive oxygen and nitrogen species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.     

Uric acid modulates vascular endothelial function through the down regulation of nitric oxide production

Abstract

Endothelial dysfunction characterized by decreased nitric oxide (NO) bioavailability is the first stage of coronary artery disease. It is known that one of the factors associated with an increased risk of coronary artery disease is a high plasma level of uric acid. However, causative associations between hyperuricaemia and cardiovascular risk have not been definitely proved. In this work, we tested the effect of uric acid on endothelial NO bioavailability. Electrochemical measurement of NO production in acetylcholine-stimulated human umbilical endothelial cells (HUVECs) revealed that uric acid markedly decreases NO release. This finding was confirmed by organ bath experiments on mouse aortic segments. Uric acid dose-dependently reduced endothelium-dependent vasorelaxation. To reveal the mechanism of decreasing NO bioavailability we tested the effect of uric acid on reactive oxygen species production by HUVECs, on arginase activity, and on acetylcholine-induced endothelial NO synthase phosphorylation. It was found that uric acid increases arginase activity and reduces endothelial NO synthase phosphorylation. Interestingly, uric acid significantly increased intracellular superoxide formation. In conclusion, uric acid decreases NO bioavailability by means of multiple mechanisms. This finding supports the idea of a causal association between hyperuricaemia and cardiovascular risk.     

The Potential Beneficial Role of Glucagon-like Peptide-1 in Endothelial Dysfunction and Heart Failure Associated with Insulin Resistance

Endothelial dysfunction is a major characteristic of the atherosclerotic process and can be used to predict the outcome of cardiovascular disease in humans. Together with obesity and insulin resistance, such dysfunction is common among patients with type 2 diabetes and may explain their poor prognosis in connection with such a disease. Insulin resistance in skeletal muscle, adipose tissue, and the liver, a well-characterized feature of obesity and type 2 diabetes, contributes to the impairment of glucose homeostasis. Furthermore, the myocardial muscle can also be resistant to insulin, which might, at least in part, explain the frequent development of heart failure in individuals suffering from type 2 diabetes. The relationship between insulin resistance and endothelial dysfunction has prompted investigations, which reveal that regular exercise, dietary changes, and/or pharmacological agents can both increase insulin sensitivity and improve endothelial function. Glucagon-like peptide-1, an incretin, lowers blood levels of glucose and offers a promising new approach to the treatment of type 2 diabetes mellitus. Its extensive extra-pancreatic effects, including a favorable influence on cardiovascular parameters, are extremely interesting in this connection. The potential pharmacological effects of glucagon-like peptide-1 and its analogues on the endothelium and the heart are discussed in the present review.     

Is NO the king? Pathophysiological benefit with uncertain clinical impact

NO is the "hero" molecule of the last few decades. It is a ubiquitous and omnipotent radical with both hemodynamic and antiproliferative effects within the cardiovascular system. NO is an important counterregulatory factor for vasoconstrictors and growth promoting substances. Endothelial dysfunction with decreased NO production is related to many cardiovascular disorders, such as coronary artery disease, heart failure and hypertension. Despite the important role of NO within the circulation, there is only limited evidence in the form of large clinical trials that NO delivery can reduce cardiovascular morbidity and mortality. Thus, NO donors are not in the first line therapy in ischemic heart disease, heart failure or arterial hypertension and NO delivery is recommended only in particular clinical situations, when a well established treatment is contraindicated or has an insufficient effect. It is concluded that the insufficient NO production is the principal disorder in endothelial dysfunction, which is related to cardiovascular pathology with deteriorated prognosis, but the impact of therapeutically increased NO bioactivity on the morbidity and mortality is inferior to well established treatment with ACE-inhibitors, AT(1) receptor blockers, beta-blockers, statins and certain antihypertensive drugs. There is little doubt that NO is king in the circulation, but kings seldom decide the battles.     

Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture)

Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A2, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.     

Cardiovascular Risk Factors Have Larger Impact on Endothelial Function in Self-Reported Healthy Women than Men in the HUNT3 Fitness Study

Background

Several studies suggest that cardiovascular risk factors comprising the metabolic syndrome have larger effects on the development of cardiovascular disease in women than in men. A recent study in self-reported healthy subjects demonstrated a marked gender difference in endothelial dysfunction that may be an important precursor of manifest cardiovascular disease. The aim of the present study was to determine whether the association between endothelial function and cardiovascular risk factors is different in self-reported healthy women compared to self-reported healthy men.

Methods and Results

Associations between endothelial function (flow mediated dilation, FMD, of the brachial artery measured by ultrasound), anthropometric variables, peak oxygen uptake (VO_2peak), blood pressure, serum lipids, blood glucose and a questionnaire on general health and lifestyle including smoking status were studied by logistic and linear regression in 2 528 women and 2 211 men aged 20–89 years, free from self-reported cardiovascular disease. In women with hyperglycemia, endothelial dysfunction (FMD ≤0%) occurred twice as frequently as in male counterparts. The presence of the metabolic syndrome, high blood pressure and low VO_2peak increased the prevalence of endothelial dysfunction more in women than in men.

Conclusion

Endothelial dysfunction is more strongly associated with cardiovascular risk factors in self-reported healthy women than in self-reported healthy men. This finding could explain why the metabolic syndrome, and especially hyperglycemia, is associated with higher cardiovascular risk and a worse prognosis in women.     

Endothelial dysfunction as a cellular mechanism for vascular failure

The regulation of vascular tone, vascular permeability, and thromboresistance is essential to maintain blood circulation and therefore tissue environments under physiological conditions. Atherogenic stimuli, including diabetes, dyslipidemia, and oxidative stress, induce vascular dysfunction, leading to atherosclerosis, which is a key pathological basis for cardiovascular diseases such as ischemic heart disease and stroke. We have proposed a novel concept termed "vascular failure" to comprehensively recognize the vascular dysfunction that contributes to the development of cardiovascular diseases. Vascular endothelial cells form the vascular endothelium as a monolayer that covers the vascular lumen and serves as an interface between circulating blood and immune cells. Endothelial cells regulate vascular function in collaboration with smooth muscle cells. Endothelial dysfunction under pathophysiological conditions contributes to the development of vascular dysfunction. Here, we address the barrier function and microtubule function of endothelial cells. Endothelial barrier function, mediated by cell-to-cell junctions between endothelial cells, is regulated by small GTPases and kinases. Microtubule function, regulated by the acetylation of tubulin, a component of the microtubules, is a target of atherogenic stimuli. The elucidation of the molecular mechanisms of endothelial dysfunction as a cellular mechanism for vascular failure could provide novel therapeutic targets of cardiovascular diseases.     

Effect of Aging and Dietary Salt and Potassium Intake on Endothelial PTEN (Phosphatase and Tensin Homolog on Chromosome 10) Function

Aging promotes endothelial dysfunction, defined as a reduction in bioavailable nitric oxide (NO) produced by the endothelial isoform of nitric oxide synthase (NOS3). This enzyme is critically regulated by phosphorylation by protein kinase B (Akt), which in turn is regulated by the lipid phosphatase, PTEN. The present series of studies demonstrated a reduction in bioavailable NO as the age of rats increased from 1 to 12 months. At 12 months of age, rats no longer demonstrated increases in phosphorylated NOS3 in response to high dietary salt intake. Endothelial cell levels of PTEN increased with age and became refractory to change with increased salt intake. In contrast to the reduction in NO production, endothelial cell production of transforming growth factor-ß (TGF-ß) relative to NO increased progressively with age. In macrovascular endothelial cells, PTEN was regulated in a dose-dependent fashion by TGF-ß, which was further regulated by extracellular [KCl]. When combined with prior studies, the present series of experiments suggested an integral role for PTEN in endothelial cell pathobiology of aging and an important mitigating function of TGF-ß in endothelial PTEN regulation. The findings further supported a role for diet in affecting vascular function through the production of TGF-ß and NO.     

TRP channels in endothelial function and dysfunction

Endothelial cells produce various factors that regulate vascular tone, vascular permeability, angiogenesis, and inflammatory responses. The dysfunction of endothelial cells is believed to be the major culprit in various cardiovascular diseases, including hypertension, atherosclerosis, heart and renal failure, coronary syndrome, thrombosis, and diabetes. Endothelial cells express multiple transient receptor potential (TRP) channel isoforms, the activity of which serves to modulate cytosolic Ca(2+) levels ([Ca(2+)](i)) and regulate membrane potential, both of which affect various physiological processes. The malfunction and dysregulation of TRP channels is associated with endothelial dysfunction, which is reflected by decreased nitric oxide (NO) bioavailability, inappropriate regulation of vascular smooth muscle tonicity, endothelial barrier dysfunction, increased oxidative damage, impaired anti-thrombogenic properties, and perturbed angiogenic competence. Evidence suggests that dysregulation of TRPC4 and -C1 results in vascular endothelial barrier dysfunction; malfunction of TRPP1 and -P2 impairs endothelial NO synthase; the reduced expression or activity of TRPC4 and -V1 impairs agonist-induced vascular relaxation; the decreased activity of TRPV4 reduces flow-induced vascular responses; and the activity of TRPC3 and -C4 is associated with oxidative stress-induced endothelial damage. In this review, we present a comprehensive summary of the literature on the role of TRP channels in endothelial cells, with an emphasis on endothelial dysfunction.     

Urocortin: a beneficial or detrimental agent to endothelium?

As a member of the corticotropin-releasing factor (CRF) family, urocortin (UCN) has been demonstrated to show diverse effects on cardiovascular system. It is commonly considered as a protective agent on vascular function. However, a growing body of evidence suggests that some effects of UCN may lead to endothelial dysfunction (ED) which may be the cause or consequence of vascular disease and a hallmark of known cardiovascular risk factors. The present review is then focused on recent evidence that reveals the beneficial and detrimental effects of UCN on endothelium.     

Modulation of endothelial nitric oxide by plant-derived products

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is recognised as a central anti-inflammatory and anti-atherogenic principle in the vasculature. Decreased availability of NO in the vasculature promotes the progression of cardiovascular diseases. Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, may improve vascular function by enhancing NO bioavailability. In this article we first outline common pathways modulating endothelial NO production or bioavailability to provide a basis for subsequent mechanistic discussions. Then we comprehensively review natural products and plant extracts known to positively influence eNOS activity and/or endothelial function in vitro or in vivo.We will discuss red wine, highlighting polyphenols, oligomeric procyanidins (OPC) and resveratrol as modulators of endothelial NO production. Other dietary products and their active components known to activate eNOS include cocoa (OPC and its monomer (?)-epicatechin), pomegranates (polyphenols), black and green tea (flavanoids, especially epigallocatechin gallate), olive oil (oleic acid and polyphenols), soy (genistein), and quercetin, one of the most abundant flavonoids in plants. In addition, phytomedical preparations made from ginkgo, hawthorn and ginseng, as well as formulations used in traditional Chinese Medicine, have been shown to affect endothelial NO production. Recurring phytochemical patterns among active fractions and purified compounds are discussed.In summary, there is increasing evidence that several single natural products and plant extracts influence endothelial NO production. Identification of such compounds and characterisation of their cellular actions may increase our knowledge of the regulation of endothelial NO production and could provide valuable clues for the prevention or treatment of cardiovascular diseases.     

The L-arginine nitric oxide pathway: avenue for a multiple-level approach to assess vascular function

Endothelial dysfunction is an early stage of atherosclerosis and has been attributed to impaired nitric oxide (NO) bioactivity and enhanced formation of oxygen-derived free radicals. Given that endothelial dysfunction is at least in part reversible, the assessment of altered NO availability is of important diagnostic and prognostic significance. Identification of such alterations may help to target asymptomatic individuals who are at risk for cardiovascular diseases and would likely benefit from preventive measures. Focusing on a single signaling pathway, we present here a multi-level approach for the early diagnosis of cardiovascular diseases by assessing molecular, biochemical, structural, and functional changes in the vascular wall.     

Endothelial Function and Serum Concentration of Toxic Metals in Frequent Consumers of Fish

Background

Endothelial dysfunction is involved in the pathogenesis of atherosclerosis. Consumption of fish is associated with reduced cardiovascular risk, but there is paucity of data concerning its effect on endothelial function. Furthermore, investigation of the effects of fish consumption on health must take into account the ingestion of contaminants, including transition metals and some metalloids, which may have unfavorable effects on health, including those on the cardiovascular system. We investigated the association between fish consumption, endothelial function (flow mediated dilation of the brachial artery), and serum concentration of some toxic metals in apparently healthy people.

Methods

Twenty-nine high fish consumers (at least 3 portions a week) were compared with 25 low fish consumers (less than 1 portion a week). All participants were free of diabetes, cardiovascular or other systemic diseases. Serum metal (antimonium, arsenic, mercury, lead, cobalt, copper, zinc, selenium, strontium) concentrations were measured in subgroups of 24 high fish consumers and 19 low fish consumers.

Results

Both groups exhibited similar habitual dietary patterns, age and anthropometric characteristics. The high fish consumers had higher flow mediated dilation (9.7±1.8 vs. 7.3±1.9%; P<0.001), but also higher serum concentrations of mercury (5.87±2.69 vs. 1.65±1.10 mcg/L; P<0.001) and arsenic (6.04±3.25 vs. 2.30±1.58 mcg/L; P<0.001). The fasting plasma glucose concentrations were significantly correlated with both mercury (r = 0.39; P = 0.01) and arsenic concentrations (r = 0.55; P<0.001).

Conclusions

Habitual consumption of high amounts of fish is associated with better endothelial function despite higher serum concentrations of mercury and arsenic.     

Endothelial senescence after high-cholesterol, high-fat diet challenge in baboons

Increasing evidence indicates that replicative senescence and premature endothelial senescence could contribute to endothelial dysfunction. This study aims at testing the hypothesis that a high-fat diet may lead to premature vascular endothelial senescence in a nonhuman primate model. We isolated endothelial cells from left and right femoral arteries in 10 baboons before and after a 7-wk high-fat dietary treatment. We compared the morphological alterations, replicative capacities, and senescence-associated beta-galactosidase activities (SA-beta-gal) at these two time points. We found that high-fat diet increased the prevalence of endothelial senescence. Endothelial replicative capacities declined dramatically, and SA-beta-gal activities increased significantly in postdietary challenge. There was no change in telomeric length using quantitative flow fluorescence in situ hybridization analysis, suggesting that some stressors lead to cell senescence independent of telomere dysfunction. Our findings that high-fat diet causes endothelial damage through the premature senescence suggest a novel mechanism for the diet-induced endothelial dysfunction.     

Effect of Dietary Docosahexaenoic Acid Supplementation on the Participation of Vasodilator Factors in Aorta from Orchidectomized Rats

Benefits of n-3 polyunsaturated fatty acids (PUFAs) against cardiovascular diseases have been reported. Vascular tone regulation is largely mediated by endothelial factors whose release is modulated by sex hormones. Since the incidence of cardiovascular pathologies has been correlated with decreased levels of sex hormones, the aim of this study was to analyze whether a diet supplemented with the specific PUFA docosahexaenoic acid (DHA) could prevent vascular changes induced by an impaired gonadal function. For this purpose, control and orchidectomized rats were fed with a standard diet supplemented with 5% (w/w) sunflower oil or with 3% (w/w) sunflower oil plus 2% (w/w) DHA. The lipid profile, the blood pressure, the production of prostanoids and nitric oxide (NO), and the redox status of biological samples from control and orchidectomized rats, fed control or DHA-supplemented diet, were analyzed. The vasodilator response and the contribution of NO, prostanoids and hyperpolarizing mechanisms were also studied. The results showed that orchidectomy negatively affected the lipid profile, increased the production of prostanoids and reactive oxygen species (ROS), and decreased NO production and the antioxidant capacity, as well as the participation of hyperpolarizing mechanisms in the vasodilator responses. The DHA-supplemented diet of the orchidectomized rats decreased the release of prostanoids and ROS, while increasing NO production and the antioxidant capacity, and it also improved the lipid profile. Additionally, it restored the participation of hyperpolarizing mechanisms by activating potassium. Since the modifications induced by the DHA-supplemented diet were observed in the orchidectomized, but not in the healthy group, DHA seems to exert cardioprotective effects in physiopathological situations in which vascular dysfunction exists.