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Biomedical subjects

B Frei

Publications and source records attributed to B Frei.

At least 55 records · Page 3Linked to original sources
PubMed1999

Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration.

Lecithin:cholesteryl acyltransferase (LCAT) deficiency resulting from targeted disruption of the Lcat gene in the mouse is associated with dramatic decreases in HDL concentration and the accumulation of nascent HDL in the plasma. We examined whether LCAT deficiency in mice is associated with a concomitant decrease in two antioxidative enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In control Lcat (+/+) mice both these enzymes are transported on HDL. Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94% and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71% decrease in PAF-AH activity and in a 58% decrease in PON activity. Apolipoprotein J (apoJ) levels, rather than being decreased, were significantly (P = 0.01) higher (36%) in Lcat (-/-) than in Lcat (+/+) mice, and the apo J/PON ratio was 3-fold greater in Lcat (-/-) than in Lcat (+/+) animals. Even though apolipoprotein A-I (apoA-I) concentration and PON activity were drastically reduced, there was no reduction in apoA-I and PON liver mRNA levels suggesting that post-transcriptional events are responsible for the reduction of plasma PON and apoA-I levels. Fast protein liquid chromatography (FPLC) revealed that in Lcat (+/+) mice both PON and PAF-AH activity is associated with large, apoA-I-containing HDL particles (9.7 nm by non-denaturing gradient gel electrophoresis) while in Lcat (-/-) mice both enzymes are associated with small 8.2 nm particles. We conclude that the concomitant reduction in HDL and apoA-I concentrations and PON and PAF-AH activities is best explained by rapid clearance of the small HDL particles found in LCAT deficiency.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

L-2-Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease.

The effective action of endothelium-derived nitric oxide (EDNO) is impaired in patients with atherosclerosis. This impairment has been attributed in part to increased vascular oxidative stress. EDNO action is improved by administration of ascorbic acid, a water-soluble antioxidant. Ascorbic acid is a potent free-radical scavenger in plasma, and also regulates intracellular redox state in part by sparing cellular glutathione. We specifically investigated the role of intracellular redox state in EDNO action by examining the effect of L-2-oxo-4-thiazolidine carboxylate (OTC) on EDNO-dependent, flow-mediated dilation in a randomized double-blind placebo-controlled study of patients with angiographically proven coronary artery disease. OTC augments intracellular glutathione by providing substrate cysteine for glutathione synthesis. Brachial artery flow-mediated dilation was examined with high-resolution ultrasound before and after oral administration of 4.5 g of OTC or placebo in 48 subjects with angiographically documented coronary artery disease. Placebo treatment produced no change in flow-mediated dilation (7.0+/-3.9% vs. 7.2+/-3.7%), whereas OTC treatment was associated with a significant improvement in flow-mediated dilation (6.6+/-4.4% vs. 11.0+/-6.3%; P = 0.005). OTC had no effect on arterial dilation to nitroglycerin, systemic blood pressure, heart rate, or reactive hyperemia. These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.

Administration, Oral↗
PubMed1998

Medicinal plants in Mexico: healers' consensus and cultural importance.

Medicinal plants are an important element of indigenous medical systems in Mexico. These resources are usually regarded as part of a culture's traditional knowledge. This study examines the use of medicinal plants in four indigenous groups of Mexican Indians, Maya, Nahua, Zapotec and - for comparative purposes - Mixe. With the first three the methodology was similar, making a direct comparison of the results possible. In these studies, the relative importance of a medicinal plant within a culture is documented using a quantitative method. For the analysis the uses were grouped into 9-10 categories of indigenous uses. This report compares these data and uses the concept of informant consensus originally developed by Trotter and Logan for analysis. This indicates how homogenous the ethnobotanical information is. Generally the factor is high for gastrointestinal illnesses and for culture bound syndromes. While the species used by the 3 indigenous groups vary, the data indicate that there exist well-defined criteria specific for each culture which lead to the selection of a plant as a medicine. A large number of species are used for gastrointestinal illnesses by two or more of the indigenous groups. At least in this case, the multiple transfer of species and their uses within Mexico seems to be an important reason for the widespread use of a species. Medicinal plants in other categories (e.g. skin diseases) are usually known only in one culture and seem to be part of its traditional knowledge.

Culture↗
PubMed1998

Medical ethnobotany of the Zapotecs of the Isthmus-Sierra (Oaxaca, Mexico): documentation and assessment of indigenous uses.

The Zapotec inhabitants of the Sierra de Oaxaca foothills (Mexico) live in an area of great botanic diversity. In daily subsistence and in response to illness, plants play a major role. An inventory of the Zapotec medicinal ethnobotany was carried out during 17 months of fieldwork. A total of 3611 individual responses concerning medicinal and non-medicinal uses for 445 different species of plants were documented. For the subsequent semi-quantitative analysis of data, the uses were grouped into ten categories and the responses for each species were summed up in each of these ten groups to yield rank-ordered lists. For the high rank-ordered and, hence, culturally important species, an assessment of the therapeutic potential was conducted using ethnobotanical, phytochemical and pharmacological data in the literature. Studies confirming the attributed properties or a scientific explanation of therapeutic use, as well as toxicological data, are still lacking for many of these species. The quantitative approach described will be the basis for future studies on the pharmacology and phytochemistry of Zapotec medicinal species. Finally, these data should also serve as a basis for biodiversity conservation and community development.

Ethnobotany↗
PubMed1998

Low plasma ascorbic acid independently predicts the presence of an unstable coronary syndrome.

OBJECTIVES: This study sought to investigate the relations between plasma antioxidant status, extent of atherosclerosis and activity of coronary artery disease. BACKGROUND: Previous studies indicate that increased antioxidant intake is associated with decreased coronary disease risk, but the underlying mechanisms remain controversial. METHODS: Plasma samples were obtained from 149 patients undergoing cardiac catheterization (65 with stable angina, 84 with unstable angina or a myocardial infarction within 2 weeks). Twelve plasma antioxidant/oxidant markers were measured and correlated with the extent of atherosclerosis and the presence of an unstable coronary syndrome. RESULTS: By multiple linear regression analysis, age (p < 0.001), diabetes mellitus (p < 0.001), male gender (p < 0.001) and hypercholesterolemia (p = 0.02) were independent predictors of the extent of atherosclerosis. No antioxidant/oxidant marker correlated with the extent of atherosclerosis. However, lower plasma ascorbic acid concentration predicted the presence of an unstable coronary syndrome by multiple logistic regression (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40 to 0.89, p = 0.01). The severity of atherosclerosis also predicted the presence of an unstable coronary syndrome (OR 1.7, 95% CI 1.14 to 2.47, p = 0.008) when all patients were considered. When only patients with significant coronary disease were considered (at least one stenosis >50%), ascorbic acid concentration (OR 0.56, 95% CI 0.37 to 0.85, p = 0.008) and total plasma thiols (OR 0.52, 95% CI 0.34 to 0.80, p = 0.004) predicted the presence of an unstable coronary syndrome, whereas the extent of atherosclerosis did not. CONCLUSIONS: These data are consistent with the hypothesis that the beneficial effects of antioxidants in coronary artery disease may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed disease.

Aged↗
PubMed1998

Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke.

A large body of experimental research indicates that the generation of free radicals leading to oxidative stress plays a role in the pathogenesis of ischemic brain injury, but evidence in humans is limited. We examined plasma levels of lipid hydroperoxides (measured as cholesteryl ester hydroperoxides, CEOOH) and ascorbic acid in 32 patients with cortical stroke, as compared with 13 patients with lacunar infarct. Patients with cortical stroke had significantly increased levels of CEOOH, which peaked on Day 5 after the ictus. Small decreases in ascorbic acid concentrations were not significant. There was a significant positive correlation of CEOOH with the NIH stroke scale, and a significant negative correlation with the Glasgow coma scale. Concentrations of CEOOH were significantly higher in patients with total anterior cerebral syndrome as compared with patients with partial anterior cerebral syndrome or posterior cerebral syndrome. Stroke volumes computed from CT or MRI scans were significantly correlated with plasma CEOOH levels. These findings implicate oxidative stress in ischemic brain injury in humans and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.

Aged↗
PubMed1998

Early high dose antioxidant vitamins do not prevent bronchopulmonary dysplasia in premature baboons exposed to prolonged hyperoxia: a pilot study.

The antioxidant vitamins ascorbic acid (AA) and alpha-tocopherol (alpha-TP) effectively inhibit oxygen free radical-induced lipid peroxidation. Using a premature baboon model of hyperoxia-induced bronchopulmonary dysplasia (BPD), we measured concentrations of AA, alpha-TP, and conjugated dienes (CD, marker of lipid peroxidation) in four animals (hyperoxic antioxidant group) receiving high dose antioxidant vitamin supplementation (AA, 100 mg x kg x(-1) x d(-1); alpha-TP; 20 mg x kg x(-1) x d(-1)) and one animal receiving standard dose antioxidant vitamin supplementation (AA, 10 mg x kg x(-1) x d(-1); alpha-TP, 1 mg x kg x(-1) x d(-1)). Respiratory and histopathologic data were compared with data from 10 historical animals exposed to hyperoxia (hyperoxic control group) and 11 historical animals treated as required with oxygen (normoxic control group) who had received standard dose antioxidant vitamin supplementation. Compared with standard dose antioxidant vitamin supplementation, high dose antioxidant vitamin supplementation effectively raised AA concentrations in plasma (37 +/- 22 micromol/L and 395 +/- 216 micromol/L, respectively) and tracheal aspirates (62 +/- 35 micromol/L and 286 +/- 205 micromol/L, respectively), and alpha-TP concentrations in plasma (10.1 +/- 2.5 micromol/L and 24.6 +/- 17.5 micromol/L, respectively). However, there was no apparent effect on tracheal aspirate CD concentrations (482 +/- 333 micromol/L and 1050 +/- 1111 micromol/L, respectively), and respiratory parameters in the hyperoxic antioxidant group were comparable to those of the hyperoxic control group but significantly worse than in the normoxic control group. Finally, no protective effect of high dose antioxidant vitamin supplementation was noted at the histopathologic level.

Animals↗
PubMed1997

Antioxidants and atherosclerotic heart disease.

Epidemiologic studies have provided evidence of an inverse relation between coronary artery disease and antioxidant intake, and vitamin E supplementation in particular. The oxidative-modification hypothesis implies that reduced atherosclerosis is a result of the production of LDL that is resistant to oxidation, but linking the reduced oxidation of LDL to a reduction in atherosclerosis has been problematic. Several important additional mechanisms may underlie the role of antioxidants in preventing the clinical manifestations of coronary artery disease (Fig. 2). Specifically, there is evidence that plaque stability, vasomotor function, and the tendency to thrombosis are subject to modification by specific antioxidants. For example, cellular antioxidants inhibit monocyte adhesion, protect against the cytotoxic effects of oxidized LDL, and inhibit platelet activation. Furthermore, cellular antioxidants protect against the endothelial dysfunction associated with atherosclerosis by preserving endothelium-derived nitric oxide activity. We speculate that these mechanisms have an important role in the benefits of antioxidants.

Animals↗
PubMed1997

Antioxidant activity of vitamin C in iron-overloaded human plasma.

Vitamin C (ascorbic acid, AA) can act as an antioxidant or a pro-oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma. Thus, it has been hypothesized that the combination of AA and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F2-isoprostanes, stable lipid peroxidation end products. However, F2-isoprostane levels were not different between those infants with BDI (138 +/- 51 pg/ml, n = 19) and those without (126 +/- 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 +/- 0.31 and 0.68 +/- 0.13 nmol/mg protein, respectively). Incubation of BDI-containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (</=10 nM cholesteryl ester hydroperoxides) as long as AA concentrations remained high. Furthermore, when excess iron was added to adult plasma, BDI became detectable, and endogenous AA was rapidly oxidized. Despite this apparent interaction between excess iron and endogenous AA, there was no detectable lipid peroxidation as long as AA was present at >10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA delayed the onset of iron-induced lipid peroxidation in a dose-dependent manner. These findings demonstrate that in iron-overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or BDI alone, causes oxidative damage to lipids and proteins in vivo.

Adult↗
PubMed1997

'Spontaneous' genetic damage in man: evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status.

The 'spontaneous' frequency of genetic damage (normal background) and the possible relationship of this damage to nutritional variables in humans were investigated in 22 subjects using several indices of genetic damage. The subjects were chosen, out of 122 initially analyzed, for being at the extremes of the highest and lowest values of one index of genetic damage, the frequency of micronucleated erythrocytes in peripheral blood. This index reflects chromosomal damage and loss in bone marrow erythropoietic cells. The assay for micronuclei is convenient but is restricted to splenectomized individuals because the human spleen removes micronucleated cells. The initial 122 subjects were splenectomized, but all were normal and healthy at the time of this study and none had a previous history of neoplastic disease. Factors investigated were stability of micronucleus frequency as a function of time, correlations among multiple markers of genetic damage, and influence on damage indices of nutritional variables, including blood levels of folate, B12 and antioxidant vitamins. Among different individuals, the range of values was 10-fold or more in the erythrocyte micronucleus, glycophorin A, plasma ascorbate and urinary 8-hydroxydeoxyguanosine (oxo8dG) assays, was approximately 6-fold in the lymphocyte micronucleus assay, and was 2-fold in the lymphocyte sister chromatid exchange (SCE) assay. Red blood cell folate and plasma folate, B12 and alpha-tocopherol values varied by up to 10-fold among individuals. Micronucleus frequencies in erythrocytes and peripheral blood lymphocytes ranged from < 0.3 to 16.9/1000 in mature red blood cells, < 1 to 33/1000 in reticulocytes, and 2.5 to 15/1000 in binucleate lymphocytes. Frequencies of glycophorin A variant erythrocytes ranged from 5.6 to 77.3 x 10(6) N/0 cells and 3.2 to 16.2 x 10(6) N/N cells, and oxo8dG excretion varied from 32 to 397 pmol/kg/day. Although a wide range of values was observed in each genetic endpoint, the extreme values for various endpoints of genetic damage were not observed in the same individuals. The frequency of micronucleated erythrocytes varied over time within individuals and indicated that individuals with the highest levels of damage exhibit greater variability than those with lower levels. In some subjects, frequencies of micronucleated erythrocytes changed dramatically over an interval of 2-3 years: four subjects with initial micronucleated reticulocyte frequencies of 20.4, 5.9, 6.4 and 33/1000 changed to 2.5, 20.5, 18.5 and 12/1000, respectively. Among more than 150 individuals we have studied, including the 64 individuals studied by Everson et al. [(1988) J. Natl. Cancer Inst., 80, 525-529] and Smith et al. [(1990) Cancer Res., 50, 5049-5054], the seven individuals with the highest observed frequencies of micronucleated erythrocytes all had exceptionally low values of plasma folate, red cell folate, or plasma B12, suggesting that folate and B12 status are the major determinants of the types of damage that lead to spontaneous micronucleus formation in erythrocytic cells.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Physiological thiol compounds exert pro- and anti-oxidant effects, respectively, on iron- and copper-dependent oxidation of human low-density lipoprotein.

The effects of thiol compounds on oxidation of human low-density lipoprotein (LDL, 0.2 mg of protein/ml) by Cu2+ or Fe3+ (10 microM, each) were investigated in an in vitro system. L-Cysteine (CYS, 25 microM-1 mM) inhibited Cu2+-dependent, but facilitated Fe3+-dependent, oxidation of LDL in a dose-dependent manner. D,L-Homocysteine (HCY, 1 mM) and glutathione (GSH, 1 mM) similarly inhibited Cu2+-dependent, while facilitating Fe3+-dependent, oxidation of LDL. However, the effectiveness of these thiols (CYS, HCY, and GSH; 1 mM each) at mediating either Cu(2+)- or Fe3+-dependent LDL oxidation was not equivalent. Thus, Cu2+-dependent oxidation of LDL was most effectively inhibited by GSH, an intermediate effect was observed with HCY, and CYS was least effective. In contrast, a reversal of this pattern was observed for facilitation of Fe3+-dependent oxidation of LDL, with CYS being most effective and GSH being least effective. Interestingly, although the disulfides cystine and homocystine (0.5 mM, each) were without effect on either Cu(2+)- or Fe3+-dependent LDL oxidation, both glutathione disulfide (GSSG, 0.5 mM) and methionine (1 mM), an S-methylated derivative of HCY, inhibited Cu2+-dependent oxidation of LDL. However, neither GSSG nor methionine had any effect on Fe3+-dependent oxidation of LDL. Thus, while a free (reduced) thiol group is important for stimulation of Fe3+-dependent oxidation of LDL by CYS, HCY, and GSH, inhibition of Cu2+-dependent oxidation of LDL by these compounds seems to be thiol-independent. Our results show that thiol compounds differentially mediate Cu(2+)- and Fe3+-dependent LDL oxidation, an important early event in atherogenesis. Mediation of metal ion-dependent LDL oxidation by thiol compounds may have important implications for the etiology of atherosclerosis and may help explain the recent epidemiologic observation that plasma HCY concentration is an independent risk factor for cardiovascular disease.

Copper↗
PubMed1997

Increased levels of plasma cholesteryl ester hydroperoxides in patients with subarachnoid hemorrhage.

The pathophysiology of subarachnoid hemorrhage (SAH) may involve free radical production and lipid peroxidation. We examined plasma levels of cholesteryl ester hydroperoxides (CEOOH) and antioxidants in 25 patients with SAH, and 10 neurologic controls with lacunar stroke. Patients with SAH had significantly increased plasma levels of CEOOH, which peaked on day 5 after the ictus. Concentrations of CEOOH were significantly increased, and ascorbic acid concentrations were significantly decreased in patients who developed vasospasm compared with patients without vasospasm. Increased levels of CEOOH were associated with increased mortality and correlated with clinical outcome scales. These results implicate oxidative stress in the pathogenesis of SAH and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.

Adult↗
PubMed1997

Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit.

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.

Animals↗
PubMed1997

Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation.

Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent on local activity of superoxide dismutase (SOD). We examined the effects of chronic inhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary copper restriction. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient animals, Cu-deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as estimated by lucigenin chemiluminescence (both P < .05). Compared with Cu-sufficient animals, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDNO agonist, but only 1.5-fold less sensitive to A23187, a receptor-independent EDNO agonist, and only 1.25-fold less sensitive to authentic NO (all P < .05). In contrast, acute inhibition of CuZnSOD with 10 mM diethyldithiocarbamate produced a more uniform reduction in sensitivity to acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P < .001). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-esterified F2-isoprostanes, a stable marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R = -.83; P < .0009) but not A23187 or authentic NO. From these findings, we conclude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arterial relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interrupts receptor-mediated stimulation of EDNO.

Acetylcholine↗
PubMed1997

Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells.

Oxidative modification of LDL by vascular cells has been proposed as a mechanism by which LDL becomes atherogenic. Antioxidants that can prevent LDL oxidation may therefore act as antiatherogens. We used endothelial cells (ECs) from human aortas (HAECs), human saphenous veins (HSECs), and bovine aortas (BAECs) to investigate the role of intracellular and extracellular vitamin C (ascorbate) in EC-mediated LDL modification. Incubation of LDL (0.1 mg protein per milliliter) with confluent HAECs in Ham's F-10 medium led to time-dependent modification of the lipoprotein. In contrast, incubation of LDL with HAECs in medium 199, which does not contain redox-active transition metal ions, did not lead to LDL modification. Both HAEC-mediated and cell-free LDL modifications in Ham's F-10 medium were strongly inhibited in a time- and dose-dependent manner by physiological concentrations of ascorbate. Confluent HAECs cultured under conventional conditions contained very little intracellular ascorbate (< 0.5 nmol/mg protein) but could be loaded with up to 20 nmol ascorbate per milligram protein in a time- and concentration-dependent manner. Ascorbate-loaded HAECs exhibited a lower capacity to modify LDL than did non-ascorbate-loaded control cells. When LDL was incubated with HSECs instead of HAECs, similar time- and concentration-dependent inhibitory effects on LDL modification of intracellular and extracellular ascorbate were observed. In contrast to human ECs, BAECs did not take up vitamin C and therefore only coincubation but not preincubation with ascorbate inhibited BAEC-mediated LDL modification. Our data show that enrichment of human vascular ECs with vitamin C lowers their capacity to modify LDL. In addition, extracellular vitamin C strongly inhibits EC-mediated, metal ion-dependent atherogenic modification of LDL.

Animals↗
PubMed1996

Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans.

BACKGROUND: Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relationship between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients. METHODS AND RESULTS: Endothelium-dependent coronary vasomotion in response to acetylcholine (10(-8) to 10(-6) mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56 +/- 9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu2+. Patients treated with lovastatin and probucol had prolongation of the lag phase (263 +/- 64 minutes) compared with diet- (91 +/- 22 minutes) or lovastatin and cholestyramine-(118 +/- 57 minutes) treated patients (P<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (P=.002), cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment. CONCLUSIONS: In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia.

Acetylcholine↗
PubMed1996

Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease.

BACKGROUND: In the setting of atherosclerosis, endothelial vasomotor function is abnormal. Increased oxidative stress has been implicated as one potential mechanism for this observation. We therefore hypothesized that an antioxidant, ascorbic acid, would improve endothelium-dependent arterial dilation in patients with coronary artery disease. METHODS AND RESULTS: Brachial artery endothelium-dependent dilation in response to hyperemia was assessed by high-resolution vascular ultrasound before and 2 hours after oral administration of either 2 g ascorbic acid or placebo in a total of 46 patients with documented coronary artery disease. Plasma ascorbic acid concentration increased 2.5-fold 2 hours after treatment (46+/-8 to 114+/-11 micromol/L, P=.001). In the prospectively defined group of patients with an abnormal baseline response (<5% dilation), ascorbic acid produced marked improvement in dilation (2.0+/-0.6% to 9.7+/-2.0%), whereas placebo had no effect (1.1+/-1.5% to 1.7+/-1.5%, P=.003 for ascorbic acid versus placebo). Ascorbic acid had no effect on hyperemic flow or arterial dilation to sublingual nitroglycerin. CONCLUSIONS: Ascorbic acid reverses endothelial vasomotor dysfunction in the brachial circulation of patients with coronary artery disease. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in patients with atherosclerosis and that endothelial dysfunction may respond to antioxidant therapy.

Adult↗