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Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased p-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and [beta]-amyloid (A[beta]) are linked with vascular disease development and increased BACE1 and A[beta] accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased A[beta], and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A[beta]42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A[beta]42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A[beta]42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A[beta]42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A[beta]42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A[beta]42. Lowering A[beta]42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes., Introduction There is increasing evidence that links vascular disease and endothelial dysfunction (as found in obesity, diabetes, and hypercholesterolemia; i.e., metabolic syndrome) with Alzheimer's disease (AD) and cognitive impairment, through [...]

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from l-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives. [ABSTRACT FROM AUTHOR]

Background-Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and Results-We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O2·-) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O2·- generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O2·- generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O2·- in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O2·-. These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. Conclusions-This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O2·- through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. [ABSTRACT FROM AUTHOR]

The radial artery is prone to vasospasm after coronary bypass surgery, and endothelial dysfunction is likely to be a key factor. We investigated whether endothelial dysfunction in radial artery conduits is present, and can be identified, preoperatively using a simple noninvasive ultrasound test of radial artery endothelial response, flow-mediated dilatation (FMD). The study population consisted of 126 patients scheduled for coronary artery bypass grafting. The afternoon before operation, patients had noninvasive ultrasound assessment of endothelial function in the left radial artery by FMD, which measures change in arterial size after an increase in flow—an endothelial-dependent response. Surplus graft segments were obtained at operation and nitric oxide bioavailability within the vessels determined from ex vivo responses to acetylcholine. Preoperative FMD in the radial artery was associated with vasorelaxations to acetylcholine in radial artery grafts (p <0.001 for both dose-response curves and maximum relaxations), although there was weak borderline association between FMD and vasorelaxations of saphenous vein grafts (p = 0.07 for dose-response curves and p <0.05 for maximum relaxations). In multivariate analysis including cardiac risk factors, FMD was a predictor of vasorelaxations of radial artery grafts (β = 0.020, SE = 0.009, p = 0.030), independent of classic risk factors for atherosclerosis. In conclusion, there is significant interindividual variation in the endothelial function of vessels used for coronary artery bypass surgery, particularly the radial artery. These differences are present and can be identified preoperatively by FMD. [Copyright &y& Elsevier]

Summary: Background & aim: Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. Methods: In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30g), as red wine (264ml), white wine (264ml), beer (633ml), whisky (79ml) or water (250ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4h after alcohol consumption. Results: Reactive hyperemia was significantly increased 1h after beer and red wine consumption (p <0.05 for both), while it returned at baseline at 4h (p =ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p <0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. Conclusions: Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults. [Copyright &y& Elsevier]

Objectives: Our purpose was to examine the impact of diabetes mellitus (DM) on vasoreactivity and endothelial function of radial artery (RA) grafts ex vivo. Background: The arteriopathy associated with DM may influence the surgeon’s choice of conduits for revascularization. Arterial conduits and especially the RA are prone to vasospasm in the perioperative period. Methods: The study population consisted of 98 patients with coronary artery disease undergoing coronary artery bypass grafting by using RA grafts. The maximum contractions of RA segments induced by K+ (66 mmol/l) and clinically important vasoconstrictors such as adrenaline (5 × 10−5 mol/l), angiotensin II (10−6 mol/l), and prostaglandin F2α (PGF2α) (10−6 mol/l) were recorded. Relaxation of RA rings to carbachol (10−4 mol/l) was used as a measure of endothelial function. Multivariate analysis was then applied to determine the role of clinical characteristics on the vasomotor responses to these agents. Results: Vessels from patients with DM had greater contractions in response to adrenaline (p < 0.05), angiotensin (p < 0.05), and PGF2α (p < 0.01) compared with non-DM vessels, despite the similar vasoconstrictions induced by high K+ (p = NS). Diabetes mellitus was also associated with smaller vasorelaxations in response to carbachol (p < 0.001). In multivariate analysis, DM was an independent predictor of RA contractions in response to adrenaline (β [SE] 3.085 [1.410], p = 0.031), angiotensin II (β [SE] 3.838 [1.552], p = 0.015), and PGF2α (β [SE] 4.609 [1.908], p = 0.018) but not K+ (p = NS). Diabetes mellitus was also independently associated with the vasorelaxations in response to carbachol (β [SE] −15.645 [2.622], p = 0.0001). Conclusions: Diabetes mellitus is associated with impaired endothelial function and greater contractions of RA grafts in response to all of the clinically relevant vasoconstrictors. These findings suggest that the RA of diabetic patients may be more prone to spasm in response to endogenous vasoconstrictors, an observation with important implications for surgeons’ choice of conduits in this cohort of patients. [Copyright &y& Elsevier]

Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature may improve the long-term outcome in healthy individuals, high-risk subjects, or patients with advanced atherosclerosis. Several therapeutic strategies are now available, targeting both the synthesis and oxidative inactivation of nitric oxide (NO) in human vasculature. Statins seem to be currently the most powerful category of these agents, improving endothelial function and decreasing cardiovascular risk after long-term administration. Other cardiovascular agents improving endothelial function in humans are angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, which increase NO bioavailability by modifying the rennin-angiotensin-aldosterone system. Newer therapeutic approaches targeting endothelial dysfunction in specific disease states include insulin sensitizers, L-arginine (the substrate for endothelial NO synthase [eNOS]) as well as substances that target eNOS “coupling,” such as folates or tetrahydrobiopterin. Although there are a variety of strategies to improve NO bioavailability in human endothelium, it is still unclear whether they have any direct benefit at a clinical level. [ABSTRACT FROM AUTHOR]

Purpose of this study was to investigate the effect of combined administration of antioxidant vitamins C and E on endothelial function and serum levels of inflammatory markers such as tumor necrosis factor α (TNF-α), interleukines 1b (IL-1b) and 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin in chronic smokers. Forty-three smokers were randomly divided into four groups receiving vitamin C 2 g/day (group A), vitamin C 2 g/day plus vitamin E 400 IU/day (group B), vitamin C 2 g/day plus vitamin E 800 IU/day (group C) or no antioxidant treatment (group D), for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) was expressed as the percentage change from baseline to post reactive hyperemia blood flow. RH% was significantly increased in groups B (P<0.05) and C (P<0.01), but remained unaffected in groups A and D. Serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1 were significantly reduced in group C (P<0.05, respectively), but remained unaffected in groups A, B and D. Thus, short term administration of vitamins C (2 g/day) and E (800 IU/day) reduces serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1, and improves forearm vasodilatory response to reactive hyperemia in healthy young smokers, while monotherapy with vitamin C alone is ineffective. [Copyright &y& Elsevier]

Abstract: Endothelial nitric oxide synthase (eNOS), the main source of endothelium-derived nitric oxide (NO), appears to be a rational therapeutic target in atherosclerosis. The exact mechanisms regulating eNOS protein expression in human vasculature are still under intensive investigation. Recent evidence suggests that statin treatment induces the expression of eNOS in vascular endothelium, leading to a respective improvement of endothelial function. Among other mechanisms, it seems that statins increase eNOS protein levels in the vasculature, partly by up-regulating klotho protein expression. This novel observation is consistent with several lines of clinical evidence suggesting that statins have antiatherogenic effects in human vasculature, by mechanisms other than lipid-lowering. [Copyright &y& Elsevier]

Abstract: Aspirin is a powerful anti-platelet drug widely used in patients with coronary atherosclerosis, but its side effects and especially its toxicity for gastrointestinal tract limit its usefulness in specific groups of patients. A new category of agents, nitric oxide-releasing aspirins (such as NCX-4016), seems to provide an alternative solution. Although this drug is still at phase II clinical trials, it has provided promising results until now. When administered in vivo, it is separated into an aspirin moiety and an NO-donating complex, providing both the antithrombotic effect of aspirin and the gastroprotective effect of NO. Additionally, it increases NO bioavailability as a vascular level, and it may have the antiatherogenic properties of endogenously produced NO. Finally, recent evidence suggests that it may also improve functional aspects of vein grafts used in CABG, with possible benefit on graft patency. However, the outcome of the large ongoing trials is needed before any conclusion is made about the role of NO-releasing aspirins in cardiovascular disease. [Copyright &y& Elsevier]

Abstract: Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the peripheral circulation, home to sites of injury, and incorporate into foci of neovascularization, thereby improving blood flow and tissue recovery. Patients with cardiovascular diseases, including coronary artery disease, heart failure, hypertension, and diabetes, have been shown to exhibit reduced number and functional capacity of EPCs. Considerable evidence indicates that EPCs constitute an important endogenous system to maintain endothelial integrity and vascular homeostasis, while reduced number of EPCs has recently been shown to predict future cardiovascular events. Thus, enhancement of EPCs could be of potential benefit for individuals with cardiovascular diseases. The interplay between inflammation and oxidative stress is involved in the initiation, progression, and complications of cardiovascular diseases. Emerging evidence from in vitro and clinical studies suggests that inflammatory and oxidative changes influence EPC mobilization. Drugs with anti-inflammatory and antioxidant properties, currently administered to patients with cardiovascular diseases, such as statins, have been demonstrated to exert beneficial effects on EPC biology. A better understanding of the inflammatory and oxidative mechanisms leading to the numerical and functional impairment of EPCs would provide additional insight into the pathogenesis of cardiovascular disease and create novel therapeutic targets. [Copyright &y& Elsevier]

L-Arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L-Arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin- 1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case-control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: l-Arginine is the substrate of endothelial nitric oxide synthase (eNOS) and the main precursor of nitric oxide (NO) in the vascular endothelium. l-Arginine improves endothelial function in patients with hypercholesterolemia, hypertension and smokers, while its role in diabetes remains unclear. Oral supplementation of l-arginine leads to a significant improvement of endothelium-dependent forearm vasodilation in hypercholesterolemic patients, while intravenous infusion of l-arginine improves endothelial function in healthy smokers. l-Arginine has anti-hypertensive properties, although its effects on endothelial function in hypertensive patients needs further evaluation. In conclusion, l-arginine administration may be useful in patients with premature atherosclerosis. [Copyright &y& Elsevier]

Background--The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. Methods and Results--Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. Conclusions--Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. [ABSTRACT FROM AUTHOR]

Background—An altered nitric oxide-redox balance has been implicated in the pathogenesis of atrial fibrillation (AF). Statins inhibit NOX2-NADPH oxidases and prevent postoperative AF but are less effective in AF secondary prevention; the mechanisms underlying these findings are poorly understood. Methods and Results—By using goat models of pacing-induced AF or of atrial structural remodeling secondary to atrioventricular block and right atrial samples from 130 patients undergoing cardiac surgery, we found that the mechanisms responsible for the NO-redox imbalance differ between atria and with the duration and substrate of AF. Rac1 and NADPH oxidase activity and the protein level of NOX2 and p22phox were significantly increased in the left atrium of goats after 2 weeks of AF and in patients who developed postoperative AF in the absence of differences in leukocytes infiltration. Conversely, in the presence of longstanding AF or atrioventricular block, uncoupled nitric oxide synthase activity (secondary to reduced BH4 content and/or increased arginase activity) and mitochondrial oxidases accounted for the biatrial increase in reactive oxygen species. Atorvastatin caused a mevalonate-reversible inhibition of Rae 1 and NOX2-NADPH oxidase activity in right atrial samples from patients who developed postoperative AF, but it did not affect reactive oxygen species, nitric oxide synthase uncoupling, or BH4 in patients with permanent AF. Conclusions—Upregulation of atrial NADPH oxidases is an early but transient event in the natural history of AF. Changes in the sources of reactive oxygen species with atrial remodeling may explain why statins are effective in the primary prevention of AF but not in its management. [ABSTRACT FROM AUTHOR]

Abstract: Background: l-arginine, the substrate for endothelial nitric oxide synthase, is essential for normal endothelial function. Aim of the present study was to investigate in healthy smokers the effect of a short-term daily l-arginine administration on vascular function. Methods: We studied the effect of a 3-day oral administration of l-arginine in 10 healthy smokers (24.3±0.73 years old) on 3 occasions (day0, day1 and day3). The study was carried out on two separate arms, one with l-arginine (7 gr/d) and one with placebo according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after (Sm0) and 20 min after (Sm20) cigarette smoking. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Results: Compared to placebo, l-arginine led to an increase of FMD (p <0.05 at day 2), indicating a favorable effect on endothelial function, which however lost significance at day 3. l-arginine induced a progressive decrease of PWV and AIx at both day 2 and day 3 (p <0.01 vs baseline for all). l-arginine blunted the acute smoking-induced increase of AIx at both day 1 (p <0.05) and day 3 (p <0.01), and there was a trend to protect the smoking-induced change of PWV at day 3 (p <0.1). Conclusions: Short-term daily administration of l-arginine improves arterial performance in healthy smokers and abrogates the smoking-induced increase in arterial stiffness and wave reflections in these individuals. [Copyright &y& Elsevier]

Abstract: Endothelial dysfunction is thought to play a major role in the development and clinical complications of heart failure. Endothelial progenitor cells (EPCs) have been shown to provide an endogenous repair mechanism to counteract detrimental risk factor-induced effects and replace dysfunctional endothelium. The number and in vitro function of EPCs is altered in patients with heart failure, as a result of its pathophysiological mechanisms. EPCs could represent a substitutional marker to guide preventive or therapeutic interventions in this disease. Enhancing the number and functional capacity of EPCs with targeted interventions may elicit functional improvement in individuals with heart failure. However, the exact role of EPCs in heart failure and their potential therapeutic implications still remain to be elucidated. [Copyright &y& Elsevier]