Search PubMed⌕ Search

Biomedical subjects

H Esterbauer

Publications and source records attributed to H Esterbauer.

At least 109 records · Page 6Linked to original sources
PubMed1992

Inhibition of LDL oxidation by antioxidants.

Low density lipoprotein (LDL) consists of about 3000 fatty acids (50% polyunsaturated) and a single molecule apolipoprotein B (500 kDa). The endogenous antioxidants of LDL consist mainly of tocopherols and few carotenoids, which protect the PUFAS against oxidation. That native LDL contains traces of oxidation products has not been proved yet. Oxidatively modified LDL (oLDL) exhibits cytotoxic and chemotactic activities, furthermore it leads to foam cell formation, a critical step in atherogenesis. The oxidation of LDL is a free radical process and leads to various aldehydic products. The oxidation of LDL is initiated by cells as well as by transition metals like Cu2+. In both cases the oxidation goes through three consecutive phases. The lag-phase is characterized by minimal degradation of PUFAs but a loss of the antioxidants. Thereafter the PUFAs are oxidized to lipid hydroperoxides, which are only intermediates (propagation-phase). These intermediates will decompose to aldehydic products, accompanied by several additional changes in the LDL particle (decomposition-phase). For increased macrophage uptake oLDL must reach the late decomposition-phase; the presence of lipid hydroperoxides in LDL is not sufficient. It is suggested that binding of aldehydes to free amino groups of Apo B is the reason for macrophage uptake. This is supported by the finding that antibodies against aldehyde-modified LDL are able to recognize oxidized LDL in atherosclerotic lesions. Antioxidants like alpha-tocopherol are able to protect LDL against oxidation. The duration of the lag-phase shows a linear relationship with the content of alpha-tocopherol in LDL. Yet the efficiency of alpha-tocopherol to protect LDL shows strong individual variation.

Animals↗
PubMed1992

Human plasma lipid peroxide levels show a strong transient increase after successful revascularization operations.

This study was performed to evaluate the hypothesis that oxygen radicals/lipid peroxidation are involved in reperfusion injury in humans. The study included 37 patients, who underwent surgical revascularization operations for kidney transplantation (9 subjects) or limb salvage (28 subjects). Peripheral venous blood samples were taken 30 min before starting reperfusion (baseline) and 1, 2, 3, 4, and occasionally 6 to 18 h after revascularization. The amount of plasma malonaldehyde formed in the reaction with thiobarbituric acid (MDA-TBA) was determined by high-performance liquid chromatography (HPLC). The baseline MDA-TBA values of the patients were very close to the value determined for 20 age-matched healthy subjects (i.e. mean +/- SD 0.689 +/- 0.294 nmol/mL plasma [range 0.2 to 1.37] vs. 0.700 +/- 0.209 nmol/mL plasma [range 0.385 to 1.29]). All patients responded to successful revascularization with significant increase of the plasma MDA-TBA within about 1 h after onset of reperfusion. Thereafter the values decreased nearly to the preoperative state. The mean increase of MDA-TBA was 107% in kidney transplantation and 54% in limb revascularization. In a few patients with severe arteriosclerosis, revascularization was not optimal and no increase in the MDA-TBA value occurred. The results of this study indicate that therapeutic intervention to prevent lipid-peroxidation-mediated reperfusion injury is confined to a rather narrow time window and must be undertaken either prior to or immediately after revascularization.

Aged↗
PubMed1992

The role of lipid peroxidation and antioxidants in oxidative modification of LDL.

The purpose of this study is to provide a comprehensive survey on the compositional properties of LDL (e.g., lipid classes, fatty acids, antioxidants) relevant for its susceptibility to oxidation, on the mechanism and kinetics of LDL oxidation, and on the chemical and physico-chemical properties of LDL oxidized by exposure to copper ions. Studies on the occurrence of oxidized LDL in plasma, arteries, and plaques of humans and experimental animals are discussed with particular focus on the use of poly- and monoclonal antibodies for immunochemical demonstration of apolipoprotein B modifications characteristic for lipid peroxidation. Apart from uptake of oxidized LDL by macrophages, studies describing biological effects of heavily or minimally oxidized LDL are only briefly addressed, since several reviews dealing with this subject were recently published. This article is concluded with a section on the role of natural and synthetic antioxidants in protecting LDL against oxidation, as well as some previously unpublished material from our laboratories.

Animals↗
PubMed1991

Role of oxidative stress in age dependent hepatocarcinogenesis by the peroxisome proliferator nafenopin in the rat.

Recently old rats were found to be much more susceptible than young rats to the hepatocarcinogenic effect of a 55-59-week treatment with the peroxisome proliferator nafenopin (NAF) (B. Kraupp-Grasl, W. Huber, H. Taper, and R. Schulte-Hermann, Cancer Res., 51: 666-671, 1991). In the present study indicators of oxidative stress were measured in the livers of the same animals (male Wistar). NAF enhanced peroxisomal beta-oxidation 10-12-fold and reduced glutathione peroxidase activity by 40-50%. Indicators of lipid peroxidation like thiobarbituric acid reactive substances and malondialdehyde were both decreased by one-third and two-thirds, respectively. Of the oxidation-sensitive polyunsaturated fatty acids linoleic acid and docosahexaenoic acid were decreased by 40% and two-thirds, respectively, but the particularly sensitive arachidonic acid remained unchanged. Taken together these data suggest that NAF did not significantly enhance lipid peroxidation in the present experiment. All NAF effects were of the same magnitude in the old and young animals. Therefore, the considerably stronger induction of hepatocarcinoma by NAF in the old animals was not associated with evidence of enhanced oxidative stress. These findings are consistent with the hypothesis that NAF acts hepatocarcinogenically by promotion of tumor development from preneoplastic lesions occurring spontaneously with age.

Age Factors↗
PubMed1991

Oxidation of lipoprotein Lp(a). A comparison with low-density lipoproteins.

Aimed at identifying possible mechanisms of the suggested high atherogenicity of Lp(a), its susceptibility for Cu(II)-induced oxidation was studied and compared with that of LDL. Since the content of antioxidants as well as the fatty acid pattern of a lipoprotein greatly affects its oxidizability, Lp(a) and LDL were characterized first with respect to these substances. Paired samples of low-density lipoproteins (LDL) and Lp(a) were isolated from seven individual donors and compared with each other. This study showed that LDL and Lp(a) are very similar with respect to their fatty acid and antioxidant composition. LDL contains approx. 1132 nmol of total fatty acids/mg lipoprotein and LDL 1466 nmol total fatty acids/mg lipoprotein. Analysis of the fatty acid composition of individual lipid classes (cholesteryl esters, phospholipids and triacylglycerols) revealed also a high similarity in the composition of these lipid classes between the two lipoproteins. A comparison of the antioxidant composition showed that Lp(a) contains less alpha-tocopherol than LDL (1.6 +/- 0.35 nmol/mg vs. 2.1 +/- 0.25 nmol/mg LDL). In copper(II)-induced lipid peroxidation experiments we found a striking difference in the susceptibility of individual lipoprotein classes between all donors. In addition, Lp(a) exhibited a 1.2 to 2.4 longer lag-phase than the corresponding LDL preparation from the same blood donor. Treatment of Lp(a) with neuraminidase resulted in a drastic decrease of the lag-phase of Lp(a). Neuraminidase treatment of LDL on the other hand had no significant effects on its susceptibility to oxidation. Supplementation of neuraminidase-treated Lp(a) with N-acetylneuraminic acid (NANA) at concentrations comparable to the naturally occurring amounts of NANA in the Lp(a) protein moiety led to an increase of the lag-phase yielding values which were comparable to those observed with native Lp(a). These results demonstrate that the fatty acid composition as well as the antioxidant concentrations of Lp(a) and LDL are quite similar; despite this fact, Cu2(+)-mediated oxidation of Lp(a) is retarded in comparison to LDL which might be due to the higher content of NANA in Lp(a).

Adult↗
PubMed1991

Experimental studies on the mechanism of action of 4-hydroxy-2,3-trans-nonenal, a lipid peroxidation product displaying chemotactic activity toward rat neutrophils.

The effects of 4-hydroxy-2,3-trans-nonenal (HNE) and nonanal on the activity of phosphoinositide-specific phospholipase C of rat neutrophils have been studied in parallel with their action on neutrophil oriented migration. Concentrations of HNE ranging from 10(-7) to 10(-5) M significantly stimulated the oriented migration of rat polymorphonuclear leukocytes. HNE stimulated both the basal and GTP gamma S-induced phospholipase C activity when used at concentrations between 10(-8) and 10(-6) M. Nonanal was devoid both of chemotactic activity and of any action on phospholipase C activity. The effect of GTP gamma S on the stimulation of phospholipase C induced by HNE was higher when the lowest dose of the aldehyde was used; the finding of an additive effect between 10(-8) M HNE and 2 x 10(-5) M GTP gamma S suggests that the two compounds may share a final common pathway of action. These results suggest that the chemotactic activity of HNE might be mediated, like that of other more well-known chemoattractants, by the stimulation of phosphoinositide-specific phospholipase C.

Aldehydes↗
PubMed1991

Determination of fatty acids in the main lipoprotein classes by capillary gas chromatography: BF3/methanol transesterification of lyophilized samples instead of Folch extraction gives higher yields.

The amount of individual fatty acids contained in the main human lipoproteins VLDL, LDL, lipoprotein (a), HDL2, and HDL3 were determined by two different methods. In Method I, the lipids were first extracted by the classical Folch procedure and then transesterified with BF3/methanol and separated by capillary GC. In Method II the lipoprotein solution was freeze dried prior to transesterification with BF3/methanol. In all lipoproteins except VLDL significantly more fatty acids were found with Method II as compared to Method I. For total fatty acids the increase was up to 17.5%, for polyunsaturated fatty acids up to 24.5%. The total fatty acid content determined by Method II resembled closely the content independently derived from the enzymatically determined lipid composition. The results indicate that in case of lipoproteins quantification of fatty acids should be made with freeze-dried samples rather than with Folch extracts.

Blood Proteins↗
PubMed1991

Elevated serum neopterin levels in atherosclerosis.

Plasma levels of neopterin were determined in patients with different clinical stages of atherosclerosis. Non-hospitalized patients with atherosclerosis had serum and plasma neopterin levels within the normal range of the assay (6 +/- 2 nM). These values were not significantly different from those reported for healthy blood donors (5 +/- 2 nM). In contrast, about 50% (29 out of 61) of hospitalized patients undergoing conservative or surgical therapy had neopterin plasma levels, which exceeded the normal range (greater than 10 nM) up to 10-fold. The two groups differ on a significance level of P less than 0.01. For further evaluation hospitalized patients were subgrouped according to neopterin levels. In the subgroup with elevated neopterin levels patients with higher Frederickson types of atherosclerosis were overrepresented compared to patients with normal neopterin levels. Type 4 differed significantly from patients without pathological changes of lipoprotein (P less than 0.05). Only 3 patients suffered from minimal skin necrosis, two of them had elevated neopterin levels. Significantly more patients with peripheral artery occlusions had elevated neopterin levels than patients with occlusions of central arteries (P less than 0.05). All other criteria used for comparison (sex, age, smoking, antioxidant status, diabetes, hypertension, adipositas, hyperuricemia) did not vary significantly in both subgroups. These data indicate that neopterin plasma levels might be a valuable parameter in activity staging and therapeutic follow up of atherosclerotic patients. Additionally, an involvement of the nonspecific immune system in atherogenesis is suggested by the increased plasma neopterin concentrations.

Aged↗
PubMed1991

Hydroxynonenal, a component of clastogenic factors?

Exposure of human lymphocyte cultures to superoxide generated by the xanthine-xanthine oxidase (X-XO) system, resulted in formation of a clastogenic factor (CF), as expected from previous work. We speculated that arachidonic acid (AA), the major polyunsaturated fatty acid of biological membranes, was oxidized via the cyclooxygenase-lipoxygenase pathways or nonenzymatically by oxygen free radicals in the culture medium to products with clastogenic properties. In the present study, we analyzed CF for AA-derived products and tested corresponding commercial standards for their clastogenic properties. The results show that prostaglandins, thromboxane, and H(P)ETEs were not increased in supernatants from X-XO treated cultures compared to untreated cultures. Synthetic H(P)ETEs added to the medium of lymphocyte cultures were only slightly or not clastogenic. In contrast hereto, the degradation product 4-hydroxynonenal was found in 50% of CF samples, while it was absent in all 43 control samples. The kinetics of detectability in the culture medium was similar to that of CF. Also, the clastogenic effect of synthetic 4-hydroxynonenal at concentrations as low as 0.1 microM suggested that this aldehyde, known for its genotoxic effects, was a clastogenic component of CF. The indirect action mechanisms of 4-hydroxynonenal via inactivation of functional SH groups in DNA polymerases, may explain why chromatid-type damage is predominant in lymphocytes exposed to CF in the Go-G1 phase of the cell cycle. This particularly was already stressed 20 years ago in the first observations of radiation-induced CF. However, 4-hydroxynonenal is not the only clastogenic component of CF.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehydes↗
PubMed1991

Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.

Lipid peroxidation often occurs in response to oxidative stress, and a great diversity of aldehydes are formed when lipid hydroperoxides break down in biological systems. Some of these aldehydes are highly reactive and may be considered as second toxic messengers which disseminate and augment initial free radical events. The aldehydes most intensively studied so far are 4-hydroxynonenal, 4-hydroxyhexenal, and malonaldehyde. The purpose of this review is to provide a comprehensive summary on the chemical properties of these aldehydes, the mechanisms of their formation and their occurrence in biological systems and methods for their determination. We will also review the reactions of 4-hydroxyalkenals and malonaldehyde with biomolecules (amino acids, proteins, nucleic acid bases), their metabolism in isolated cells and excretion in whole animals, as well as the many types of biological activities described so far, including cytotoxicity, genotoxicity, chemotactic activity, and effects on cell proliferation and gene expression. Structurally related compounds, such as acrolein, crotonaldehyde, and other 2-alkenals are also briefly discussed, since they have some properties in common with 4-hydroxyalkenals.

Aldehydes↗
PubMed1991

Role of vitamin E in preventing the oxidation of low-density lipoprotein.

The fatty acid composition, antioxidants, and the oxidation resistance of the low-density lipoproteins (LDL) from a number of different donors were determined. The oxidation resistance of LDL, as determined in vitro by the duration of the lag-phase in copper ion-induced oxidation, did not correlate with the alpha-tocopherol content of the LDL. By supplementating plasma with vitamin E, the alpha-tocopherol content of LDL could be increased from approximately 9 to 30 mol/mol LDL and also the oxidative resistance increased nearly linearly with increasing alpha-tocopherol content. The results indicate that alpha-tocopherol is an important, yet not the only parameter that determines the oxidation resistance of LDL.

Adult↗
PubMed1991

Time course study of lipid peroxidation induced by N2-methyl-9-hydroxyellipticinium acetate or celiptium in rat renal cortex.

Celiptium is an ellipticine derivative with renal toxic side effects. It has recently been characterized as a lipid overload in proximal tubular cells where loss of total phospholipids (in particular phosphatidylethanolamine) and of polyunsaturated fatty acids are linked to the accumulation of unsaturated free fatty acids and aldehydes. A time course study of celiptium-induced peroxidative damage showed that a single dose of 40 mg/kg of celiptium induced no change in total or individual phospholipids of rat renal cortex. On the other hand, free fatty acids and thiobarbituric acid reactive substances increased as early as 1 hr after celiptium injection. 4-Hydroxynonenal (4-HNE) also increased whereas polyunsaturated fatty acids levels decreased at 6 and 24 hr. After 24 hr no change was detected in microsomal phospholipids. In contrast, the brush-border membranes showed alterations such as decrease in total phospholipids and polyunsaturated fatty acids levels accompanied by increase in aldehydes. It appears that peroxidative damage occurs in brush-border membranes of celiptium-treated rat kidneys with preferential losses of phosphatidylethanolamine (PE, 30%) and phosphatidylcholine (PC, 14%).

Animals↗
PubMed1991

Effect of antioxidants on oxidative modification of LDL.

Human low density lipoprotein (LDL) with a molecular mass of 2.5 million contains on average 1300 molecules of polyunsaturated fatty acids (PUFAs) bound in the different lipid classes. The predominant antioxidant in LDL is alpha-tocopherol, with an average of 6 molecules in each LDL particle. The other substances with potential antioxidant activity are: gamma-tocopherol, beta-carotene, alpha-carotene, lycopene, cryptoxanthin, cantaxanthin, phytofluene and ubiquinol-10. Each is present in amounts of only 1/20th to 1/300th of that of alpha-tocopherol. If LDL is exposed to oxidative conditions (Cu++ ions, macrophages) a lag phase precedes the oxidation of PUFAs. During the lag phase the antioxidants disappear with alpha-tocopherol the first to go and beta-carotene the last. The lag phase, which can readily be determined, is an index of the oxidation resistance of LDL. If LDL is loaded with vitamin E in vitro its oxidation resistance increases linearly with its alpha-tocopherol content according to the equation, y = kx+a. The same relationship is applicable if the alpha-tocopherol content of LDL is increased by taking oral vitamin E. Daily doses of 150, 225, 800 and 1200 IU RRR-alpha-tocopherol increased the LDL alpha-tocopherol on average to 138%, 158%, 144% and 215% of the initial value, the oxidation resistance being increased to 118%, 156%, 135% and 175%, respectively. The efficiency of vitamin E-dependent (= k) and the vitamin independent (= a) oxidation resistance seem to be subject specific with strong individual variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants↗
PubMed1991

Effect of oral supplementation with D-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation.

Twelve clinically healthy subjects participated in a vitamin E supplementation study. Eight were given daily dosages of 150, 225, 800, or 1200 IU RRR-alpha-tocopherol for 21 days (two persons per dose) and four received placebo. Prior, during, and after the supplementation period, alpha-tocopherol, gamma-tocopherol, and carotenoids were determined in plasma and low density lipoprotein (LDL). The maximum levels of alpha-tocopherol were 1.7- to 2.5-times the baseline values in plasma and 1.7- to 3.1-times in LDL. A high correlation existed between alpha-tocopherol in plasma and LDL. gamma-Tocopherol significantly decreased in plasma and LDL during vitamin E supplementation. No significant influence on the lipoprotein and lipid status and carotenoid levels of the participants occurred throughout the supplementation. The resistance of LDL against copper-mediated oxidation was also measured. The oxidation resistance of LDL was significantly higher during vitamin E supplementation. However, the efficacy of vitamin E in protecting LDL varied from person to person. The statistical evaluation of all data gave a correlation of r2 = 0.51 between alpha-tocopherol in LDL and the oxidation resistance as measured by the length of the lag-phase preceding the oxidation of LDL. No association was seen between levels of carotenoids and vitamin E in plasma and LDL. The present study clearly shows that in humans the oxidation resistance of LDL can be increased by vitamin E supplementation.

Administration, Oral↗
PubMed1991

Identification of metabolic pathways of the lipid peroxidation product 4-hydroxynonenal by enterocytes of rat small intestine.

The cytotoxic lipid peroxidation product 4-hydroxynonenal (HNE1) is rapidly metabolized in enterocytes. The degradation of HNE and other aldehydic products of lipid peroxidation processes seems to be an antioxidative defense system. The metabolism of HNE was studied in suspensions of rat enterocytes at 37 degrees C, pH 7.4 and at initial HNE concentration of 100 microM. About 70% of the HNE were degraded within three minutes of incubation. Main products of HNE which were identified in enterocytes were the glutathione-HNE-1:1-conjugate, the hydroxynonenoic acid and the 1,4-dihydroxynonene. Furthermore, the formation of metabolites of the tricarboxylic acid cycle is suggested. The quantitative share of HNE binding to proteins was low with about 1% of total HNE consumption after three minutes of incubation.

Aldehydes↗