Lipid Peroxidation Metabolites Research Articles

Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum

OBJECTIVE: We tested the hypothesis that serum free (nonesterified) fatty acid and triglyceride concentrations are increased in nulliparous women with preeclampsia relative to women with uncomplicated pregnancies and that these lipids decrease post partum, consistent with the known resolution of clinical symptoms. The relationships between serum concentrations of these lipids and the lipid peroxidation metabolite malondialdehyde were also examined. STUDY DESIGN: Predelivery and 24 to 48 hour postpartum venous blood samples were collected from eight women with preeclampsia and nine women with uncomplicated pregnancies after an 8- to 10-hour fast. Sera were analyzed for concentrations of triglycerides, free fatty acids, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and malondialdehyde. RESULTS: Antepartum serum triglyceride and free fatty acid concentrations were increased approximately twofold in women with preeclampsia relative to uncomplicated pregnancies ( p < 0.02 and 0.004, respectively). Total, high-density lipoprotein, and low-density lipoprotein cholesterol concentrations did not differ between groups. Concentrations of all lipids decreased significantly in both groups within 48 hours post partum. However, triglyceride and free fatty acid concentrations remained higher in women with preeclampsia ( p < 0.006, both variables). Triglyceride and free fatty acid concentrations correlated positively, both ante partum ( R 2 0.42, p < 0.01) and post partum ( R 2 0.39, p < 0.02). Antepartum concentrations of malondialdehyde were 50% higher in women with preeclampsia ( p < 0.01) and decreased post partum ( p < 0.02) but did not decrease in controls ( p = 0.07). Antepartum serum triglycerides and free fatty acids correlated positively with malondialdehyde concentrations ( R 2 0.38, p < 0.02, in both cases). CONCLUSION: Triglycerides and free fatty acids, but not cholesterol, are increased in preeclampsia and correlate with the lipid peroxidation metabolite malondialdehyde. We speculate that these interactions may contribute to endothelial cell dysfunction in preeclampsia. (A M J O BSTET G YNECOL 1996;174:975-82.)

Lipid metabolite involvement in the activation of the human heme oxygenase-1 gene

Cellular effects of ultraviolet A (UVA) radiation include peroxidation of membrane lipids as well as a decrease in intracellular glutathione. We have investigated whether damage to membrane lipids is involved in the activation of the human heme oxygenase-1 gene by UVA. Irradiation of human skin fibroblasts in the presence of the lipophilic antioxidants, butylated hydroxytoluene and a-tocopherol, enhances the UVA-induced HO-1 mRNA accumulation, suggesting that peroxidation of plasma membrane lipids is not involved. Furthermore, sodium ascorbate, which induces lipid peroxidation mainly in the plasma membrane, induces HO-1 mRNA to low levels only. The decrease in GSH by UVA radiation is not affected by the presence of the lipophilic antioxidants while ascorbate treatment increases the intracellular GSH by twofold above controls. These results indicate that peroxidation of internal membrane lipids, a decrease in the intracellular GSH levels and the integrity of the plasma membrane are all important for the UVA-induction of heme oxygenase-1. Both nonenzymatic as well as enzymatic lipid peroxidation metabolites are inducers of heme oxygenase-1. The nonenzymatic lipid peroxidation product 4-hydroxynonenal induces heme oxygenase-1 mRNA up to 40-fold and the phospholipase metabolites diacylglycerol and arachidonic acid induce this mRNA by three-to sixfold above basal levels. We also demonstrate that the cyclooxygenase metabolites of arachidonic acid are important for the UVA-activation of the heme oxygenase-1 gene.

4-hydroxynonenal, a metabolite of lipid peroxidation, activates phospholipase D in vascular endothelial cells

We have examined the activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAEC) treated with 4-hydroxynonenal (4-HNE). Treatment of BPAEC labelled with [ 32P] orthophosphate (5 h for minimal phospholipid labelling) and [ 3H] myristic acid (24 h) with 4-HNE in the presence of 0.5% ethanol resulted in the formation of [ 3H] phosphatidylethanol (PEt) and [ 3H] phosphatidic acid (PA) with very little accumulation of [ 32P] PEt. The formation of [ 3H] PEt, as opposed to [ 32P] PEt, suggests that PEt synthesis was not through de novo pathway but rather through the PLD mechanism. 4-Hydroxynonenal-induced PLD activation was dose and time dependent, and was not associated with cytotoxicity as determined by [ 3H] deoxyglucose release. The formation of PEt was not affected by chelation of either extracellular Ca 2+ with EGTA (5 mM, 30 min) or intracellular Ca 2+ with BAPTA-AM (25 μM, 30 min). Treatment of BPAEC with either staurosporine (10 μM, 15 min), a protein kinase C (PKC) inhibitor, or down regulation of PKC by chronic 12-0-tetradecanoylphorbol-13-acetate (TPA) treatment (100 nM, 18 h) had no effect on 4-HNE-induced PLD activation. These results indicate that PLD activation by 4-HNE is independent of PKC activity. We also examined the specificity of nonylaldehyde derivatives and hydroxyalkenals on PLD activation. In addition to 4-HNE, 4-hydroxyoctenal and 4-hydroxyhexenal also stimulated [ 32P] PEt formation. Among the various nonylaldehydes examined, only trans-2-nonenal and trans-2-cis 6-nonadienal exhibited PLD activation, suggesting the requirement of a trans double bond at carbon 2 and a hydroxyl group at carbon 4. However, in contrast to 4-HNE-induced PLD activation of BPAEC monolayers, treatment of 105,000 × g membranes with 4-HNE had no effect on PLD catalyzed hydrolysis of [2- 14C] oleoyl phosphatidylcholine. These data provide evidence that 4-HNE, a metabolite of membrane lipid peroxidation, may be involved in endothelial cell signal transduction, through the activation of phospholipase D and the generation of second messengers like phosphatidic acid and diacylglycerol.

Role of activation of lipid peroxidation in the pathogenesis of experimental peritonitis

Investigation was carried out for studying the role of lipid peroxidation (LP) in the genesis of destructive process in the abdominal cavity. The model of experimental peritonitis was made on the dogs. According to the concentration of fat acids conjugates with double couplings (diene conjugates--DC), malondialdehyde (MDA) the LP activity was discovered. Simultaneously the activity of ceruloplasmin (CP), superoxide dismutase activity of plasma, total proteolytic blood activity, summary indicators of antioxidants plasma status and the level of medium-mass molecules was indicated. It was established that LP activation began in the first hours of peritonitis development yet, concentration of LP metabolites (MDA and DC) in plasma increased during disease progressing. CP and superoxide dismutase activity of plasma decreased. Total proteolytic blood activity and level of medium-mass molecules increased after the growth of LP intensity.

Dissociation of malondialdehyde mutagenicity in Salmonella typhimurium from its ability to induce interstrand DNA cross-links

Malondialdehyde (MDA), an in vivo metabolite of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in Salmonella typhimurium. It is a reactive electrophile that can form interstrand cross-links in DNA. To explore the possibility that MDA-induced interstrand cross-links are the pre-mutagenic lesion, we have quantitated the ability of highly purified preparations of MDA to form interstrand cross-links when reacted with linear plasmid DNA. At physiological temperature and pH, MDA did not form DNA cross-links as determined by DNA denaturation followed by agarose gel electrophoresis. DNA cross-links were formed, however, when incubations with MDA were carried out at either pH 4.2 or temperatures exceeding 60°. α-Methylmalondialdehyde (CH 3MDA) was found to cross-link DNA more efficiently than MDA, but was not mutagenic in any tester strain of Salmonella. MDA polymers, formed by acid incubation of MDA, also were capable of inducing cross-links. However, an inverse relationship was observed between mutagenicity and extent of polymerization. The pattern of mutagenic response for MDA in different strains of Salmonella was compared with mitomycin C, an established mutagenic cross-linking agent. Error-prone repair and a UvrB + phenotype, which are needed for the induction of mutations by mitomycin C, were not required for MDA mutagenesis. These findings, taken together, dissociate the mutagenicity of MDA from its ability to form interstrand cross-links with DNA.