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J C Fruchart

Publications and source records attributed to J C Fruchart.

At least 127 records · Page 7Linked to original sources
PubMed1998

PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter.

PPARgamma is a member of the peroxisome proliferator activated receptors (PPAR) subfamily of nuclear receptors. So far two PPARgamma isoforms, PPARgamma1 and PPARgamma2, were known in mammals. We describe the structure of a novel human PPARgamma subtype, PPARgamma3. The PPARgamma3 mRNA is transcribed from a novel promoter localized 5' of exon A2. PPARgamma3 mRNA expression was restricted to adipose tissue and large intestine. Similar to human PPARgamma1 and -2, PPARy3 is activated by thiazolidinediones and prostaglandin J derivatives and binds with high affinity to a PPRE.

5' Untranslated Regions↗
PubMed1998

Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPARalpha and PPARgamma forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARalpha is already present in undifferentiated monocytes, PPARgamma expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARalpha resides constitutively in the cytoplasm, whereas PPARgamma is predominantly nuclear localized. Transient transfection experiments indicate that PPARalpha and PPARgamma are transcriptionally active after ligand stimulation. Ligand activation of PPARgamma, but not of PPARalpha, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPARalpha and PPARgamma ligands induce apoptosis of macrophages activated with tumor necrosis factor alpha/interferon gamma. Finally, PPARgamma inhibits the transcriptional activity of the NFkappaB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFkappaB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.

Apoptosis↗
PubMed1998

The nuclear receptors peroxisome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates.

Fibrates are widely used hypolipidemic drugs which activate the nuclear peroxisome proliferator-activated receptor (PPAR) alpha and thereby alter the transcription of genes controlling lipoprotein metabolism. Fibrates influence plasma high density lipoprotein and its major protein, apolipoprotein (apo) A-I, in an opposite manner in man (increase) versus rodents (decrease). In the present study we studied the molecular mechanisms of this species-specific regulation of apoA-I expression by fibrates. In primary rat and human hepatocytes fenofibric acid, respectively, decreased and increased apoA-I mRNA levels. The absence of induction of rat apoA-I gene expression by fibrates is due to 3 nucleotide differences between the rat and the human apoA-I promoter A site, rendering a positive PPAR-response element in the human apoA-I promoter nonfunctional in rats. In contrast, rat, but not human, apoA-I transcription is repressed by the nuclear receptor Rev-erbalpha, which binds to a negative response element adjacent to the TATA box of the rat apoA-I promoter. In rats fibrates increase liver Rev-erbalpha mRNA levels >10-fold. In conclusion, the opposite regulation of rat and human apoA-I gene expression by fibrates is linked to differences in cis-elements in their respective promoters leading to repression by Rev-erbalpha of rat apoA-I and activation by PPARalpha of human apoA-I. Finally, Rev-erbalpha is identified as a novel fibrate target gene, suggesting a role for this nuclear receptor in lipid and lipoprotein metabolism.

Animals↗
PubMed1998

Selective uptake of cholesteryl esters from high-density lipoprotein-derived LpA-I and LpA-I:A-II particles by hepatic cells in culture.

Selective uptake of high-density lipoprotein (HDL)-associated cholesteryl esters (CE), i.e. lipid uptake independent of HDL particle uptake, delivers CE to the liver and steroidogenic tissues in vivo and in vitro. From human plasma HDL, two major subpopulations of particles can be isolated: one contains both apolipoprotein (apo) A-I and apo A-II (designated LpA-I:A-II) as dominant protein components, whereas in the other apo A-II is absent (LpA-I). In this study, selective CE uptake from LpA-I and LpA-I:A-II by cultured cells was investigated. LpA-I and LpA-I:A-II were isolated by immunoaffinity chromatography from human plasma high-density lipoprotein3 (HDL3, d = 1.125-1.21 g/ml) and both particles were radiolabeled in the protein (125I) as well as in the CE moiety ([3H]cholesteryl oleyl ether ([3H]CEt)). Several control experiments validated the labeling methodology applied. To investigate selective CE uptake, human Hep G2 hepatoma cells, human hepatocytes in primary culture and human skin fibroblasts were incubated in medium containing doubly radiolabeled LpA-I or LpA-I:A-II particles. Thereafter cellular tracer content was determined. For each cell type the rate of apparent lipoprotein particle uptake according to the lipid tracer ([3H]CEt) was in substantial excess over that due to the protein tracer (125I), demonstrating selective CE uptake from LpA-I as well as from LpA-I:A-II. This difference in uptake between [3H]CEt and 125I, i.e. the rate of apparent selective CE uptake, was significantly higher for LpA-I compared to LpA-I:A-II, and this was dose- as well as time-dependent. Thus in human hepatic cell and fibroblasts, CE are selectively taken up to a higher extent from LpA-I compared to LpA-I:A-II. These results may suggest that LpA-I particles of the human plasma HDL fraction may be those lipoproteins which more efficiently deliver CE to the liver via the selective uptake pathway whereas LpA-I:A-II may play a less important role.

Apolipoprotein A-I↗
PubMed1998

Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells, retinoids increased apo C-III mRNA and protein production. Transient transfection experiments indicated that retinoids increase apo C-III expression at the transcriptional level. This increased apo C-III transcription is mediated by the retinoid X receptor (RXR), since LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8, 8-pentamethyl-2-naphtalenyl)ethenyl]benzoic acid), a RXR-specific agonist, but not TTNPB ((E)- 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphtalenyl)propenyl]benzoic acid), a retinoic acid receptor (RAR)-specific agonist, induced apo C-III mRNA in HepG2 cells and primary human hepatocytes. Mutagenesis experiments localized the retinoid responsiveness to a cis-element consisting of two imperfect AGGTCA sequences spaced by one oligonucleotide (DR-1), within the previously identified C3P footprint site. Cotransfection assays showed that RXR, but not RAR, activates apo C-III transcription through this element either as a homo- or as a heterodimer with the peroxisome proliferator-activated receptor. Thus, apo C-III is a target gene for retinoids acting via RXR. Increased apo C-III expression may contribute to the hypertriglyceridemia and atherogenic lipoprotein profile observed after retinoid therapy.

Adult↗
PubMed1998

Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators.

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.

Acute-Phase Proteins↗
PubMed1998

Glucocorticoids induce the expression of the leptin gene through a non-classical mechanism of transcriptional activation.

Leptin is a hormone which is produced in adipose tissue and which plays a role in the regulation of energy homeostasis. The expression of the ob gene, encoding leptin, is under multi-hormonal control. We have shown previously that high doses of glucocorticoids are positive regulators of leptin expression in rats and that they concomitantly reduce food intake and body mass gain in these animals. In the present report we analyse the molecular mechanism of this glucocorticoid regulation of leptin expression. In cultured rat adipocytes dexamethasone induces leptin mRNA levels, an effect not inhibited by the protein synthesis inhibitor cycloheximide. In addition, our data indicate that the induction of the expression of the leptin gene by dexamethasone is at least in part due to a transcriptional activation that is mediated by the glucocorticoid receptor. Deletion mapping of the human leptin promoter shows that cis-elements involved in the glucocorticoid effect are located between -55 and +31 relative to the transcription initiation site. Since this region does not contain a binding site for the glucocorticoid receptor, the effect does not rely on the classical molecular mechanism of glucocorticoid receptor action. A role of C/EBP and Sp-1 in mediating this glucocorticoid effect was furthermore excluded. Multiple nuclear factors from 3T3-L1 preadipocytes interact with this promoter region of the human leptin gene and may be potential mediators of the induction by glucocorticoids.

3T3 Cells↗
PubMed1998

Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group.

The hypolipidemic action of fibrates has recently been shown to involve the activation of peroxisome proliferator activated receptors establishing a molecular mechanism for this class of drugs. Increasing clinical trial evidence supports the efficacy of fibrates in the treatment of dyslipoproteinemias, particularly in patients with hypertriglyceridemia and low high-density lipoproteins.

Animals↗
PubMed1998

VLDL compositional changes and plasma levels of triglycerides and high density lipoprotein.

VLDL chemical composition is related to plasma levels of triglycerides and HDL-cholesterol. We evaluated patients with primary hypertriglyceridemia with or without hypoalphalipoproteinemia and subjects with normotriglyceridemia with hypoalphalipoproteinemia. The pattern observed in all the groups was an enrichment in the triglyceride content of VLDL and in apo B-VLDL. Compared to controls, LpC-III:B levels were higher in hypertriglyceridemic patients with low or normal HDL-cholesterol levels (7.3 +/- 0.6 vs. 14.9 +/- 1.8 and 12.3 +/- 2.8 mg/dl; P < 0.005 and P < 0.01, respectively) and LpE:B concentration was only increased in patients with hypertriglyceridemia and normal HDL-cholesterol levels (3.1 +/- 0.5 vs. 6.3 +/- 1.0 mg/dl; P < 0.01). The activity of the cholesteryl ester transfer protein was higher in hypertriglyceridemic patients with low HDL-cholesterol levels than in controls (380 +/- 25 vs. 262 +/- 14% cholesteryl esters/ml.h; P < 0.001). The most atypical VLDL particle was found in patients who combined an accumulation of VLDL particles and a reduction in HDL-cholesterol concentration. These two parameters represent both ends of the cholesteryl ester-triglyceride transfer, a crucial factor for VLDL chemical composition and HDL levels.

Adult↗
PubMed1998

Branched synthetic peptide constructs mimic cellular binding and efflux of apolipoprotein AI in reconstituted high density lipoproteins.

This study investigates the suitability of the trimeric apolipoprotein (apo)AI(145-183) peptide that we recently described, to serve as a model to probe the relationship between apoAI structure and function. Three copies of the apoAI(145-183) unit, composed each of two amphipathic alpha-helical segments, were branched onto a covalent core matrix and the construct was recombined with phospholipids. A similar construct was made with the apoAI(102-140) peptide and used as a comparison with dimyristoylglycerophosphocholine (DMPC)-apoAI complexes. The DMPC-trimeric-apoAI(145-183) complexes had similar immunological reactivity with monoclonal antibodies directed against the 149-186 apoAI sequence (A44), suggesting that the A44 epitope is exposed similarly in both the synthetic peptide and the native apoAI complexes. The complexes generated with the trimeric-apoAI(145-183) bind specifically to HeLa cells with comparable affinity to the DMPC apoAI complexes; they are a good competitor for binding of apoAI to both HeLa cells and Fu5AH rat hepatoma cells; finally, these complexes promote cholesterol efflux from Fu5AH cells with an efficiency comparable with the apo AI/lipid complexes. To study LCAT activation by the trimeric apo AI(145-183) construct, complexes were prepared with dipalmitoylphosphatidylcholine (DPPC), cholesterol (C) and either the trimeric construct or apoAI. LCAT activation by the trimeric construct was much lower than by apo AI, possibly because the conformation of the trimeric 145-183 peptide in DPPC/C/peptide complexes does not mimic that of apoAI in the corresponding complexes. In comparison, the complexes generated with the multimeric apoAI(102-140) construct had a poor capacity to mimic the physico-chemical and biological properties of apoAI. The apoAI(102-140) construct had low affinity for lipid compared with the (145-183) construct. After association with lipids, it was a poor competitor of DMPC-apoAI complexes for cellular binding and had only limited capacity to promote cholesterol efflux. These results suggest trimeric constructs can serve as an appropriate models for apoAI, enabling further investigations and new experimental approaches to determine the structure-function relationship of apoAI.

Animals↗
PubMed1998

High density lipoproteins and coronary heart disease. Future prospects in gene therapy.

Atherosclerosis cardiovascular disease is the leading cause of death in industrial societies. For coronary heart disease, hypercholesterolemia and dyslipoproteinemia are the major risk factors. Low serum levels of cholesterol in the HDL fraction is the most common abnormality found in patients with confirmed coronary artery disease. A therapeutical strategy consists in increasing the serum HDL cholesterol concentration in order to improve the 'reverse cholesterol transport'. Studies in transgenic mice and rabbits for human apo A-I or human lecithin cholesterol acyl-transferase showed that overexpression of these proteins increases serum HDL cholesterol concentration and reduces diet induced atherogenesis. Furthermore, adenovirus-mediated transfer of human apo A-I and LCAT genes in mice also increases circulating apo A-I and LCAT. Apo A-I and LCAT are two potential targets for gene therapy of patients with atherosclerosis associated with a low HDL cholesterol level.

Animals↗
PubMed1998

Transcriptional control of adipogenesis.

Adipocyte differentiation is coordinatedly regulated by several transcription factors. C/EBP beta, C/EBP delta and ADD-1/SREBP-1 are active early during the differentiation process and induce the expression and/or activity of the peroxisome proliferator activated receptor-gamma (PPAR gamma), the pivotal coordinator of the adipocyte differentiation process. Activated PPAR gamma induces exit from the cell cycle and triggers the expression of adipocyte-specific genes, resulting in increased delivery of energy to the cells. C/EBP alpha, whose expression coincides with the later stages of differentiation, cooperates with PPAR gamma in inducing additional target genes and sustains a high level of PPAR gamma in the mature adipocyte as part of a feedforward loop. Altered activity and/or expression of these transcription factors might underlie the pathogenesis of disorders characterized by increased or decreased adipose tissue depots.

Adipocytes↗
PubMed1998

Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice.

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.

Adenocarcinoma↗
PubMed1998

Short term response of circulating leptin to feeding and fasting in man: influence of circadian cycle.

OBJECTIVE: To investigate whether acute feeding induces changes in circulating leptin levels in humans and whether these changes vary according to nycthemeral cycle. METHODS: First experiment. Eighteen male subjects were given a fatty meal at 08.00 h. Blood sampling was performed for 10 h following this meal. Second experiment. Thirteen male subjects were given either a mixed meal or remained fasting either at night (starting at 01.00 h) or during the day (starting at 13.00 h). Blood samples were drawn every hour for a period of 8 h. RESULTS: First experiment. Serum leptin levels increased progressively from a mean (s.d.) baseline of 3.8 +/- 2.2 ng/ml to a value of 4.5 +/- 2.7 ng/ml (P < 0.01) 8 h after the fatty meal. Second experiment. During the day, serum leptin levels increased progressively from 2.65 +/- 1.7 to 3.34 +/- 2.2 ng/ml (P < 0.001) 6 h after the test-meal and decreased from 2.68 +/- 1.5 to 1.9 +/- 1.1 ng/ml (P < 0.001) 8 h after the beginning of the fasting experiment. Similar results were obtained at night. No statistically significant differences in leptin levels were observed between day and night sessions in response to feeding (mean area under the curve: 3.0 +/- 4.1 vs 4.1 +/- 4.1 ng/ml) and fasting (-2.9 +/- 2.2 vs -1.5 +/- 2.2 ng/ml). CONCLUSION: In two independent experiments, human serum leptin levels increase following food intake. This response is not influenced by nycthemeral cycle.

Adult↗
PubMed1998

Effects of different dietary cholesterol concentrations on lipoprotein plasma concentrations and on cholesterol efflux from Fu5AH cells.

BACKGROUND: The fatty acid composition of the diet can modulate the effect of dietary cholesterol on plasma lipoproteins. However, HDL composition and its capacity to promote cholesterol efflux can be influenced by the diet. OBJECTIVE: Modifications in plasma lipids and in the capacity of serum to stimulate the cholesterol efflux induced by a low-fat diet [National Cholesterol Education Program (NCEP) Step I diet], by a monounsaturated fatty acid (MUFA)-rich diet, and by addition of cholesterol to both diets was studied. DESIGN: Fifteen young, healthy men followed 2 NCEP Step I diets (<30% of fat as energy, with <10% saturated fat and 14% MUFAs) for 24 d, providing 0.027 or 0.068 mg cholesterol x kJ(-1) x d(-1), and 2 oleic acid-enriched diets (38% of energy as fat, with 24% MUFAs) providing the same amount of dietary cholesterol as the NCEP Step I diets. RESULTS: Total cholesterol, LDL cholesterol, apolipoprotein (apo) B, and apo A-I concentrations decreased after the NCEP Step I and MUFA diets compared with the usual diet. HDL cholesterol also decreased after the NCEP Step I diet. Total:HDL cholesterol, apo B, and apo B:apo A-I were lower after the MUFA diets than after the NCEP Step I diets. There were no significant differences between the lipid profiles obtained after the NCEP Step I and MUFA diets were enriched with cholesterol. The capacity of serum to promote cholesterol efflux was significantly higher after the cholesterol-enriched NCEP Step I diet than after the NCEP Step I diet. CONCLUSIONS: The MUFA diet induced a better lipid profile than the NCEP Step I diet; however, the increase in the cholesterol content of both diets produced similar plasma lipid changes. The cholesterol in the NCEP Step I diet increased the cholesterol efflux induced by total serum.

Adult↗
PubMed1998

Cigarette smoking is associated with unhealthy patterns of nutrient intake: a meta-analysis.

The aim of this investigation was to assess the relationship between smoking status and nutrient intakes using a meta-analysis. Publications in English were sought through a Medline search using the following key words: food habits, eating, feeding behavior, diet, food, nutrition, nutritional status or assessment, tobacco use disorder, tobacco, nicotine and smoking. Scanning relevant reference lists of articles and hand searching completed the data collection. No attempt was made to search for unpublished results. Paper selection was based on nutritional surveys including comparisons of smokers with nonsmokers. Fifty-one published nutritional surveys from 15 different countries with 47,250 nonsmokers and 35,870 smokers were used in the analysis. The estimates of size effects were calculated with the mean and variance values of each nutrient intake and the size of the sample. Smokers declared significantly (all P < 10(-5)) higher intakes of energy (+4.9%), total fat (+3.5%), saturated fat (+8.9%), cholesterol (+10.8%) and alcohol (+77.5%) and lower intakes of polyunsaturated fat (-6.5%), fiber (-12.4%), vitamin C (-16.5%), vitamin E (-10.8%) and beta-carotene (-11.8%) than nonsmokers. Protein and carbohydrate intakes did not differ between smokers and nonsmokers. There was no evidence of heterogeneity among studies. In conclusion, the nutrient intakes of smokers differ substantially from those of nonsmokers. Some of these differences may exacerbate the deleterious effects of smoke components on cancer and coronary heart disease risk.

Adolescent↗
PubMed1998

A high concentration of melatonin inhibits in vitro LDL peroxidation but not oxidized LDL toxicity toward cultured endothelial cells.

The pineal hormone, melatonin, was recently found to be a potent free scavenger for hydroxyl and peroxyl radicals. Melatonin also inhibits neuronal and thymocyte damage due to oxidative stress. Atherosclerosis development is mediated by low-density lipoprotein (LDL) oxidation and the endocytosis of oxidized LDL by resident macrophages in the subendothelial vascular wall. Furthermore, the cytotoxic effect of oxidized LDL increases atherogenicity. The goal of this study was to compare the antioxidant activities of melatonin and vitamin E against in vitro LDL oxidation and their cytoprotective actions against oxidized LDL-induced endothelial cell toxicity. An attempt at loading LDL with melatonin by incubating human plasma with an ethanolic melatonin solution gave only low protection against Cu2+-induced LDL oxidation in comparison with vitamin E and gave no detectable incorporation of melatonin into LDL, measured by high-performance liquid chromatography (HPLC) coupled to UV detection. High concentrations of melatonin (10-100 microM) added to the oxidative medium induced a clear inhibition of Cu2+-induced LDL oxidation, characterized as an increase in the lag-phase duration of conjugated diene formation and decreases in the maximal rate of the propagation phase and in the maximal amount of conjugated diene formation. Determination of the median efficacious dose (ED50) of melatonin and vitamin E by their ability to increase lag-phase duration showed that melatonin was less active than vitamin E (ED50, 79 vs. 10 microM, respectively). Melatonin was also less active than vitamin E in limiting the formation of thiobarbituric acid-reactive substances (TBARS) and LDL fluorescence intensity increase in the medium during Cu2+-induced LDL oxidation. Cu2+-induced LDL oxidation in the presence of 100 microM melatonin produced oxidized LDLs that were less recognizable for the scavenger receptors of J774 macrophages than were untreated LDLs. Vitamin E, 10 microM, was more active than 100 microM melatonin in inhibiting LDL oxidation and the resulting lipoprotein alterations leading to binding internalization and degradation by the J774 macrophages. Vitamin E, 100 microM, inhibited the pursuit of the oxidation of oxidized LDL mediated by bovine aortic endothelial cells (BAECs) in a culture medium containing Cu2+, whereas 100 microM melatonin had no antioxidant effect. Melatonin, 100 microM, as well as 100 microM vitamin E inhibited intracellular TBARS formation during the incubation of BAECs with highly oxidized LDL but had no influence on the increase in glutathione (GSH) concentration during this lengthy exposure (16 h) of BAECs to highly oxidized LDL. During this period, the same dose of vitamin E but not of melatonin tended to limit the decrease in adenosine triphosphate (ATP) concentration. Vitamin E, 100 microM, did not significantly reduce cellular lactate dehydrogenase (LDH) release in the culture medium during the incubation of oxidized LDL with BAECs, whereas 100 microM melatonin dramatically increased this release. These data show that melatonin is less active than vitamin E in inhibiting in vitro LDL oxidation and does not inhibit the cytotoxicity of oxidized LDL toward cultured endothelial cells. The concentrations necessary to inhibit LDL oxidation are far beyond those found in human plasma (100 microM vs. 100 pM). Therefore our results indicate that the pineal hormone melatonin per se appears to have little antiatherogenic property in the in vitro oxidation of LDL and the cytoprotective action against the toxicity of oxidized LDL. Nevertheless, in vivo LDL oxidation takes place in the subendothelium of the artery wall, and nothing is known about the concentration of melatonin or its catabolites in this environment.

Antioxidants↗