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Results for “endothelial dysfunction”

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PubMed2005

Vascular endothelial dysfunction in diabetic cardiomyopathy: pathogenesis and potential treatment targets.

Cardiovascular complications account for significant morbidity and mortality in the diabetic population. Diabetic cardiomyopathy, a prominent cardiovascular complication, has been recognized as a microvascular disease that may lead to heart failure. Pathogenesis of diabetic cardiomyopathy involves vascular endothelial cell dysfunction, as well as myocyte necrosis. Clinical trials have identified hyperglycemia as the key determinant in the development of chronic diabetic complications. Sustained hyperglycemia induces several biochemical changes including increased non-enzymatic glycation, sorbitol-myoinositol-mediated changes, redox potential alterations, and protein kinase C (PKC) activation, all of which have been implicated in diabetic cardiomyopathy. Other contributing metabolic abnormalities may include defective glucose transport, increased myocyte fatty acid uptake, and dysmetabolism. These biochemical changes manifest as hemodynamic alterations and structural changes that include capillary basement membrane (BM) thickening, interstitial fibrosis, and myocyte hypertrophy and necrosis. Diabetes-mediated biochemical anomalies show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Studies in both animal and human diabetes have shown alteration of several factors including vasoactive molecules that may be instrumental in mediating structural and functional deficits at both the early and the late stages of the disease. In this review, we will highlight some of the important vascular changes leading to diabetic cardiomyopathy and discuss the emerging potential therapeutic interventions.

Animals↗

PubMed2003

Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.

OBJECTIVES: To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects. METHODS: Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks. RESULTS: Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups. CONCLUSIONS: In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2006

TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.

AIMS: Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. METHODS AND RESULTS: A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed. CONCLUSION: Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.

Diabetes Mellitus, Type 2↗

PubMed1999

Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Plasma levels of ADMA are elevated in individuals with hypercholesterolemia or atherosclerosis. We postulated that reduced degradation of ADMA may play a role in the accumulation of ADMA in these individuals. Accordingly, we studied the effects of oxidized LDL (oxLDL) or tumor necrosis factor-alpha (TNF-alpha) on the accumulation of ADMA by transformed human umbilical vein endothelial cells (ECV304) and on the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which degrades ADMA. METHODS AND RESULTS: ECV304 were incubated with or without native LDL (100 micrograms/mL), oxLDL (100 micrograms/mL), or TNF-alpha (250 U/mL) for 48 hours. The concentration of ADMA in the conditioned medium was determined by high-performance liquid chromatography. Western blotting was performed to evaluate DDAH expression. We assayed DDAH activity by determining L-citrulline formation from ADMA. The addition of oxLDL or TNF-alpha to ECV304 significantly increased the level of ADMA in the conditioned medium. The effect of oxLDL or TNF-alpha was not due to a change in DDAH expression but rather to the reduction of DDAH activity. To determine whether dysregulation of DDAH also occurred in vivo, New Zealand White rabbits were fed normal chow or a high-cholesterol diet. Hypercholesterolemia significantly reduced aortic, renal, and hepatic DDAH activity. CONCLUSIONS: These results suggest that the endothelial vasodilator dysfunction observed in hypercholesterolemia may be due to reduced degradation of ADMA, the endogenous inhibitor of NOS.

Amidohydrolases↗

PubMed1997

Circulating and cellular markers of endothelial dysfunction with aging in rats.

The influence of age on endothelial functional markers was investigated in rats. Angiotensin I converting enzyme (ACE) activity and nitric oxide synthase (NOS) mRNA expressions were examined in the lung and aorta of 10-, 20-, and 30-mo-old normotensive rats. These data were extended by the measurement of circulating endothelial cells. ACE activity was significantly decreased in plasma (P < 0.01) and lungs (P < 0.01) at 30 mo, whereas it was significantly increased in the aorta (P < 0.001) at this age. Conversely, ACE mRNA levels decreased with age in the lung (P < 0.05). The level of constitutive endothelial NOS (eNOS) mRNA was significantly reduced in the aorta of 30-mo-old rats (P < 0.05), but no changes were observed in the lungs. The level of inducible NOS (iNOS) mRNA in the aorta was significantly decreased in 20- and 30-mo-old rats (P < 0.01), whereas it was significantly increased in the lung at 30 mo (P < 0.01). Interestingly, eNOS was expressed approximately 30 times more (P < 0.001) in the aorta than iNOS, whereas in the lung it was only slightly higher than iNOS (35%; P < 0.001). Neuronal NOS mRNA expression was not modified with aging. In the aorta, guanosine 3',5'-cyclic monophosphate concentration followed NOS expressions and showed a significant decrease at 30 mo (P < 0.001). An increase in the number of circulating endothelial cells was observed in the oldest rats, possibly reflecting an increase in endothelial cell turnover with aging. The present results demonstrate that aging modifies the expression of endothelial markers implicated in the regulation of vasomotor tone. This age-dependent impairment of endothelial functions could contribute to the increased risk of pathological processes within the arterial wall associated with aging.

Aging↗

PubMed2001

[Relationship between endothelial dysfunction and nitric oxide production in young male smokers].

OBJECTIVES: Endothelial function in the brachial arteries is impaired in smokers. However, little is known about this condition in young adult men. The relationship between nitric oxide(NO) production and the endothelial function was investigated in young smokers and compared with non-smokers. METHODS: Flow-mediated vasodilation of the brachial artery during reactive hyperemia was examined in 10 young smokers(mean age 31 years) and 12 control subjects(mean age 28 years). The vasodilator response in the brachial artery was measured by ultrasonography, and blood samples were obtained from the right cephalic vein. Blood samples were taken at baseline, 30 sec after cuff deflation, and before and 5 min after 0.3 mg of nitroglycerin administration. Blood flow was calculated by multiplying mean flow velocity and vessel cross-sectional area. Plasma NOx(nitrate + nitrite) levels were measured, and the percentage change of NOx production(delta NOx) was calculated as follows: delta NOx(%) = [(NOx concentration at peak flow-mediated vasodilation or after 0.3 mg nitroglycerin administration) - baseline NOx concentration)] x 100/baseline NOx concentration. RESULTS: Percentage changes in diameter of the brachial artery, NOx production and delta NOx in response to nitroglycerin were not statistically different between the two groups(smokers: 27.6 +/- 8.0 mumol/l, control subjects: 34.0 +/- 8.7 mumol/l). However, percentage change of flow-mediated vasodilation during reactive hyperemia in the young smokers was significantly smaller than that in the control subjects(4.8 +/- 2.7%, 9.1 +/- 5.3%, respectively, p < 0.05). Moreover, delta NOx during reactive hyperemia in the smokers was significantly smaller than that in the control subjects(388.8 +/- 90.2%, 738.0 +/- 284.5%, respectively, p < 0.05). CONCLUSIONS: The impaired response to reactive hyperemia in young smokers might be associated with decreases in flow-dependent NO production.

Adult↗

PubMed2004

Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries.

BACKGROUND: Ultrasonographic appearances of polycystic ovaries (PCO) are found in 50% of South London Indian subcontinent Asians, a population at high risk of coronary disease and type 2 diabetes (DM). PCO is a familial condition but the genetics remain to be clarified. At present, the only characteristic documented in male family members is premature male pattern balding before the age of 30 years. Our aim was to quantify insulin resistance and endothelial cell function in the brothers of Indian subcontinent Asian women with PCO and/or a family history of type 2 DM. METHODS: Indian subcontinent Asian women (n = 40, age 16-40 years) with a brother available for study were recruited from the local population. They were stratified into four groups according to the ultrasound appearances of PCO and/or a family history of type 2 DM. Control subjects had no PCO and no family history of DM. Insulin sensitivity (KITT) was measured using a short insulin tolerance test and endothelial function using brachial artery ultrasound to measure flow-mediated dilatation (FMD). FINDINGS: Groups were well matched for age, body mass index (BMI) and waist-hip circumference ratios. Asian women with PCO demonstrated insulin resistance independent of BMI or family history of diabetes. Women with PCO and a family history of DM have reduced FMD, though PCO alone was not a marker. The brothers of women with PCO also have insulin resistance, comparable to that associated with a family history of type 2 DM. This was associated with elevations of blood pressure, abnormalities in serum lipid concentrations and impaired endothelial cell function. Endothelial cell function was particularly impaired in those subjects with both a sister with PCO and a family history of DM. INTERPRETATION: In an ethnic minority population at higher risk of coronary heart disease, brothers of women with PCO have evidence of insulin resistance and endothelial cell dysfunction in early adult life. Further study is required to establish whether these findings are associated with an increased incidence of cardiovascular events in this population.

Adolescent↗

PubMed1998

Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs.

OBJECTIVES: Inflammatory stimuli or mechanical stresses associated with hypothermic cardiopulmonary bypass could potentially impair cerebrovascular function, resulting in inadequate cerebral perfusion. We hypothesize that hypothermic cardiopulmonary bypass is associated with endothelial or vascular smooth muscle dysfunction and associated cerebral hypoperfusion. Therefore we studied the cerebrovascular response to endothelium-dependent vasodilator, acetylcholine, endothelium-independent nitric oxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newborn lambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature = 18 degrees C). METHODS: Studies were performed on 13 newborn lambs equipped with a closed cranial window, allowing for direct visualization of surface pial arterioles. Six animals were studied while undergoing hypothermic cardiopulmonary bypass, whereas seven served as nonbypass, warm (37 degrees C) controls. Pial arteriolar caliber (range = 111 to 316 microm diameter) was monitored using video microscopy. RESULTS: Topical application of acetylcholine caused a dose-dependent increase in arteriolar diameter in the control group that was absent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermic cardiopulmonary bypass did not alter the vasodilation in response to sodium nitroprusside. Furthermore, the contractile response to serotonin was fully expressed during hypothermic cardiopulmonary bypass. CONCLUSIONS: The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. It is speculated that loss of endothelium-dependent regulatory factors in the cerebral microcirculation during hypothermic cardiopulmonary bypass may enhance vasoconstriction, and impaired cerebrovascular function may be a basis for associated neurologic injury during or after hypothermic cardiopulmonary bypass.

Acetylcholine↗

PubMed1995

Carvedilol, a new beta-adrenoreceptor blocker antihypertensive drug, protects against free-radical-induced endothelial dysfunction.

We tested the ability of carvedilol, an antihypertensive beta-adrenoreceptor antagonist with antioxidant properties, to protect rat aorta rings from free-radical-induced endothelial cell (EC) dysfunction. Rings were exposed to the superoxide generator pyrogallol. Vascular function of intact rings was assessed by observing acetylcholine (ACh)-induced vasorelaxation following submaximal contraction by U-46619. Function of rings denuded of ECs was assessed by observing S-nitroso-N-acetylpenicillamine (SNAP)-induced vasorelaxation following submaximal contraction by U-46619. Carvedilol exerted a significant protective effect against pyrogallol-induced vasoconstriction (17.1 +/- 4.8 vs. 31.9 +/- 5.4% for vehicle, p < 0.05). Carvedilol also demonstrated significant protection against pyrogallol-induced endothelium dysfunction, enhancing vasorelaxation to 1,000 nmol/l ACh (73 +/- 3.9 vs. 48 +/- 3.0% vehicle, p < 0.01). These protective effects were not seen with propanolol, a pure beta-receptor antagonist. Carvedilol mixed with pyrogallol and SNAP preserved SNAP-induced vasorelaxation in rings denuded of ECs (80.4 +/- 5.3 vs. 63.7 +/- 4.8% control, p < 0.05). Carvedilol appears to protect vascular function by scavenging free radicals and enhancing the effects of NO.

Acetylcholine↗

PubMed2005

Vitamin K1 (phylloquinone) induces vascular endothelial dysfunction: role of oxidative stress.

We aimed to investigate the mechanisms underlying the vascular effects induced by phylloquinone (Vitamin K1; VK1). Vascular reactivity experiments, using standard muscle bath procedures, showed that VK1 (5 and 50 microM) enhances the contractile response of endothelium-intact, but not denuded, rat carotid rings to phenylephrine. Similarly, maximal contraction induced by phenylephrine was enhanced in the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The combination of L-NAME and VK1 did not produce any further additional effect. Pre-incubation of intact-rings with VK1 reduced both acetylcholine- and bradykinin-induced relaxation. VK1 induced an increment in tension on carotid rings submaximally pre-contracted with phenylephrine. VK1-induced increment in tension was completely abolished by endothelial removal or incubation of intact rings with L-NAME and L-NNA. Conversely, 7-nitroindazole, 1400 W, or indomethacin did not affect VK1-induced contraction. Moreover, VK1 reduced L-arginine-induced relaxation in endothelium-intact rings. Lucigenin-amplified chemiluminescence assays showed that VK1 induced an increase in the level of superoxide anions in endothelium-intact but not denuded rings. Measurement of nitrite and nitrate generation showed that VK1 did not alter nitrate formation but strongly inhibited the generation of nitrite. Finally, the superoxide anions scavenger tiron prevented the endothelial vasomotor dysfunction caused by VK1 on phenyleprine-induced contraction and acetylcholine or bradykinin-induced relaxation. In conclusion, our data show that VK1 disrupts the vasomotor function of rat carotid. Our results suggest that VK1-induced oxidative stress through production of superoxide anion is interfering with the NO pathway, which in turn is responsible for the altered vascular reactivity induced by VK1.

Animals↗

PubMed1990

Plasma free N-terminal fibronectin 30-kDa domain as a marker of endothelial dysfunction in type 1 diabetes mellitus.

The plasma free N-terminal fibronectin 30-kDa domain was measured in 44 type 1 diabetic patients and in 20 healthy subjects. A significantly raised mean concentration of a free N-terminal fibronectin 30-kDa domain was found in plasma of diabetic patients with proliferative retinopathy as compared with healthy persons (P less than 0.001). A positive correlation was observed between free N-terminal fibronectin 30-kDa domain and von Willebrand factor in plasma of all examined subjects (r = 0.62, P less than 0.01). A similar correlation was present between 30-kDa domain and albuminuria (r = 0.56, P less than 0.01). However, no relationship was found between fibronectin 30-kDa domain and control of diabetes as assessed by fructosamine concentration. The free N-terminal fibronectin 30-kDa domain may be used as a marker of actual endothelial cell dysfunction in diabetes.

Adult↗

PubMed2006

[The main determinants of endothelial dysfunction].

Nitric oxide (NO) is produced from amino acid L-arginine via the catalytic action of NO synthases, which use dioxygen and NADH or NADPH as cofactor. This simple molecule acts at nanomolar concentrations and demonstrates a wide spectrum of physiological effects, a primary of which is vasodilatation. The production of NO in endothelium cells is induced by mechanical action (increased blood-vessels wall tension) and chemical agents (catecholamines, acetylcholine, bradykinin, histamine). The endothelium-released NO easily diffuses to the underlying smooth muscles and triggers their relaxation by increasing cyclic guanosine monophosphate level and subsequent opening of endothelial potassium channels (K(ATP), K(Ca)). NO on the endothelium surface inhibits adhesion and aggregation of platelets, regulates the main functions of myocardium, modulates the permeability of endothelium, and weakens the interaction of endothelium cells and leukocytes by reducing the expression of adhesion-stimulating proteins. Direct evidence suggests that free radicals and related reactive oxygen species mostly as O2-, HO-, ONOO-, ROO- are associated with an endothelium dysfunction, which manifests itself as an impairment of endothelium-dependent vasorelaxation. Though reactive oxygen species in a small amount are produced constantly, the decreased metabolic turnover of homocysteine, poor performance of antioxidants or high level of angiotensin II alters the balance between production of free radicals and their neutralization. Such events decrease NO bioavailability and thus condition the development of various diseases like arteriosclerosis, hypertension, diabetes, heart and renal failure. Agents increasing NO bioavailability and depressing the endothelial dysfunction would be the most useful for the treatment above-mentioned pathologies.

Adult↗

PubMed1995

15-Hydroxyeicosatetraenoic acid and diabetic endothelial dysfunction in rabbit aorta.

We examined the effects of diabetes on eicosanoid metabolism and endothelium-dependent relaxation in isolated aorta from alloxan-induced diabetic rabbits and that from normal rabbits incubated in increased concentrations (44 mM) of glucose in vitro for 6 h. Immunoreactive 15-hydroxyeicosatetraenoic acid (HETE) was assayed in the incubation media of isolated aortic segments. Basal and acetylcholine (ACh)-stimulated release of 15-HETE was significantly greater in aorta of diabetic animals as compared with those of normal rabbits. Incubation of aortic segments from normal rabbits in increased concentrations of glucose caused a significant increase in basal and ACh-stimulated release of 15-HETE; and the release was significantly greater in aortic segments with endothelium than in segments without endothelium. Basal and ACh-stimulated release of 15-HETE was inhibited by indomethacin, a cyclooxygenase inhibitor. 15-HETE caused contractions of aortic rings that were inhibited by the prostaglandin H2 (PGH2) thromboxane A2 (TXA2) receptor blocker SQ-29548, but not by the TXA2 synthase inhibitor carbethoxyhexyl imidazole or indomethacin. Treatment of aortic rings with subthreshold concentrations of 15-HETE impaired ACh-induced relaxation; this was prevented by treatment with SQ-29548. Thus, abnormal release of endothelium-derived 15-HETE may play a role in endothelial cell dysfunction and increased vasoconstriction in diabetes by a mechanism that involves interaction with PGH2/TXA2 receptors.

Acetylcholine↗

PubMed2006

Functional interplay between platelet activation and endothelial dysfunction in patients with coronary heart disease.

Platelet-monocyte binding and surface P-selectin expression are sensitive markers of platelet activation. Endothelium-derived factors are known to inhibit platelet activation and may confer important anti-atherothrombotic effects. We assessed the relationship between platelet activation and endothelium-dependent vasomotion in patients with coronary heart disease (CHD). Twenty male patients with stable CHD were compared with 20 healthy men. Platelet-monocyte binding and platelet surface expression of P-selectin were assessed using two-colour flow cytometry on whole blood. Forearm blood flow was assessed in patients using venous occlusion plethysmography during intra-arterial infusions of substance P, acetylcholine and sodium nitroprusside. Platelet activation was higher in patients than healthy men (platelet-monocyte binding, 27 +/- 3 vs. 20 +/- 1%; P < 0.05). In patients with CHD, there was an inverse correlation between maximal substance P induced vasodilatation and both platelet-monocyte binding (P = 0.003) and P-selectin expression (P = 0.02). A similar correlation was observed between platelet-monocyte binding and the vasomotor response to acetylcholine (P = 0.08) but not with sodium nitroprusside. In patients with stable coronary heart disease, there is a strong inverse relationship between markers of platelet activation and endothelium-dependent vasomotor function. This may explain the pathophysiological mechanism linking endothelial vasomotor dysfunction and the risk of acute atherothrombotic events.

Analysis of Variance↗

PubMed2003

Association of asymmetric dimethylarginine and endothelial dysfunction.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), which has been characterized as an "endogenous anti-atherosclerotic molecule". Synthesis of NO can be selectively inhibited by guanidino-substituted analogs of L-arginine, which act as competitive inhibitors at the active site of the enzyme. One such analog is asymmetric dimethylarginine (ADMA), a compound that has been found in human plasma and urine and exerts the activity of an endogenous inhibitor of NO synthase. In contrast to ADMA, its regioisomer symmetric dimethylarginine (SDMA) does not inhibit NO synthase. The methyl groups contained within the dimethylarginine molecules are derived from S-adenosylmethionine, an intermediate in the homocysteine/methionine pathway. There is experimental evidence that homocysteine may affect endothelium-dependent vascular function by increasing the formation of ADMA. Both ADMA and SDMA are eliminated from the body by renal excretion. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations found in pathophysiological conditions (i.e., 3-15 microM). ADMA likely acts as an autocrine regulator of endothelial NO synthase activity. When rabbits are placed on a diet enriched with 1% cholesterol, ADMA levels are increased within 4 weeks of dietary intervention as compared to control animals. Elevated plasma concentrations of ADMA are also present in hypercholesterolemic and hypertensive patients, in patients with chronic heart failure, and in other patient groups at high risk of developing cardiovascular disease. Elevation of ADMA induces dysfunction of the endothelium, which becomes clinically evident by impaired endothelium-dependent vasodilation, hyperaggregability of platelets, and enhanced monocyte adhesion. Recent prospective studies suggest that endothelial dysfunction indicates an increased risk of future cardiovascular events. In line with these observations, we and others found evidence that ADMA is a novel cardiovascular risk factor.

Animals↗

PubMed1996

Oxidative stress and lipids in diabetes: a role in endothelium vasodilator dysfunction?

Endothelial dysfunction is a key feature of diabetes mellitus and is thought to be the major cause of vascular complications associated with the disease. The vascular endothelium demonstrates impaired synthesis of vasodilators and increased release of procoagulants and vasoconstrictors, defects which theoretically could explain the increased incidence of atherosclerosis and hypertension found within this patient group. The pathways mediating endothelial cell layer dysfunction are unknown, although many candidates have been proposed. This review concentrates on the hypothesis that increased oxidative stress combined with abnormal plasma lipid composition leads to reduced synthesis of endothelial vasodilators and hence endothelial dysfunction. Free radical generation is undoubtedly raised in diabetes but the evidence for decreased antioxidant status is debatable. The role of antioxidant and lipid-lowering therapy is considered, but few studies have directly investigated the effect of treatment on vascular function. Concern arises from individual studies of vitamin E in diabetic animals which have proved deleterious. Current literature implies that a combination therapy of vitamin E and vitamin C may be beneficial, but this needs to be investigated further in both animal and human diabetes.

Animals↗

PubMed2004

Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent.

OBJECTIVE: The mitogen-activated protein (MAP) kinase system, especially the p38 MAP kinase, is activated in chronic heart failure (CHF). However, the role of vascular p38 MAP kinase in CHF has not been analyzed yet. METHODS AND RESULTS: In aortic rings from rats with CHF 10 weeks after myocardial infarction, acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax: 54+/-5%) compared to sham-operated animals (Rmax: 77+/-5%, p<0.01), while endothelium-independent relaxation elicited by sodium nitroprusside was not significantly changed. Aortic levels of phosphorylated p38 MAP kinase protein were significantly elevated in rats with CHF. In addition, phosphorylation of MAP kinase-activated protein kinase-2 (MAPKAPK-2), an index of p38 MAP kinase activity, was increased. Aortic superoxide anion generation was significantly enhanced in rats with CHF accompanied by elevation of the NAD(P)H oxidase subunit p47phox protein expression. Inhibition of p38 MAP kinase by treatment with the p38 MAP kinase inhibitor SB239063 (800 ppm in standard rat chow) reduced MAPKAPK-2 phosphorylation, preserved acetylcholine-induced relaxation (Rmax: 80+/-4%, p<0.01), and reduced vascular superoxide formation. SB239063 treatment did not affect blood pressure and left ventricular enddiastolic pressure. In aortic tissue from CHF animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril, p38 MAP kinase phosphorylation was significantly reduced. CONCLUSIONS: Vascular p38 MAP kinase is markedly activated in rats with CHF. Chronic p38 MAP kinase inhibition with SB239063 prevented endothelial vasomotor dysfunction through reduction of superoxide anion production.

Acetylcholine↗

PubMed1999

Endothelin in coronary endothelial dysfunction early after human heart transplantation.

BACKGROUND: Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy. METHODS: We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin-mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5+/-3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. RESULTS: The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. CONCLUSION: Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.

Adult↗