Coronary risk factors and their modification: lipids, smoking, hypertension, estrogen, and the elderly.
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Lipid peroxidation and modification of lipid composition in an endothelial cell model of ischemia and reperfusion.
Among the changes that accompany the development of ischemia are alterations in the composition and turnover of membrane phospholipids. To study these effects, a cell culture model was developed to facilitate accurate measurements of lipids over varying intervals of ischemia and reperfusion (I/R). In order to mimic ischemia, rabbit aortic endothelial cells were grown to confluency on collagen coated beads and the bead cultures allowed to settle to the bottom of a conical test tube or spectrofluorometric cuvette. The cell-coated beads were then resuspended in media to simulate the process of reperfusion. Survival after ischemia/reperfusion, was determined by measurements of cellular replating efficiency, and found to decrease after periods longer than three hours of ischemia (followed by 24 h of reperfusion). Plating efficiencies were reduced to nearly 50% after 5 h of ischemia followed by reperfusion. Release of LDH inversely correlated with cell survival, and lactate production, ATP levels, and extracellular H2O2 concentration were all affected by the duration of ischemia. These changes could be directly related to rates of cellular oxygen consumption which decreased by 50% after 5 h of ischemia, while the percentage of oxygen consumption not be inhibitable by cyanide, increased. Release of esterified fatty acids, which was partly inhibited by the phospholipase A2 inhibitor, mepacrine, was stimulated by increasing periods of ischemia while the incorporation of free fatty acids into phospholipids was inhibited. The incorporation of arachidonic acid was inhibited to a lesser degree than that of oleic or linoleic acids with a resulting change in phospholipid fatty acyl composition favoring greater proportions of unsaturated fatty acids. In some experiments, the effects of vitamin E or ascorbic acid administered prior to ischemia were studied. The degree of fatty acid unsaturation, fatty acid incorporation into phospholipids, and release from phospholipids into the free fatty acid pool during ischemia/reperfusion were not affected by prior administration of vitamin E or ascorbic acid. However, the extent of lipid peroxidation during ischemia was inhibited by 100 mM ascorbic acid when present during the ischemia/reperfusion period, but not by vitamin E administered for 24 h prior to ischemia. Ascorbic acid treatment, but not vitamin E, also enabled cells to recover substantial amounts of the ATP lost following prolonged ischemia. The ATP recovery corresponded to an increased cell survival and decreased lipid peroxidation. Progressive intervals of ischemia followed by reperfusion result in compromised cell respiratory activity and decreased ATP production, and decreased phospholipid acylation leading to net hydrolysis. The associated changes in phospholipid composition, and specifically increased unsaturation appear to favor peroxidation of membrane phospholipids.
Acidosis↗
Metabolism and control of lipid structure modification.
The lipid composition characteristic of a particular cellular membrane can become significantly altered, sometimes quite suddenly, when the cell is placed under environmental stress. In the majority of cases examined, the alterations seem to return the membrane's physical state towards that existing prior to imposition of the stress. The compositional changes are often diverse in their nature and also in their site of origin within the cell. Certain modifications, such as changes in the degree of phospholipid acyl chain unsaturation and in the reordering of fatty acid pairing on specific phospholipids, are now recognized as crucial first responses to stress, while others (e.g., fluctuations in relative proportions of different phospholipid classes and in the sterol:phospholipid ratio) develop more slowly and may represent secondary adjustments to the initial lipid changes. The factors directly responsible for modifying membrane lipid composition are generally unknown at the molecular level, but recent advances provide new clues favoring involvement, in some cases, of the ubiquitous mediator Ca2+. In other cases, the physical state of a membrane may directly modulate the activity of lipid-metabolizing enzymes embedded therein.
Cell Membrane↗
Modification of membrane lipid composition following the nutritional shift-up of starved cells. A comparison with membrane biogenesis in Tetrahymena.
Detailed analyses of lipid composition have been made on various membrane fractions isolated at different intervals after 24 h-starved Tetrahymena cells were refed with nutrient-rich medium. During starvation there was a marked alteration in both phospholipid polar headgroup and acyl chain compositions: an increase in 2-aminoethylphospholipid and gamma-linolenic acid (18 : 3) with a concurrent decrease in phosphatidylethanolamine and palmitoleic acid (16 : 1). However, following refeeding, such an altered lipid composition was rather rapidly restored to the initial level of the control cell membranes prior to starvation. This membrane lipid modification was found to occur in good accordance with the recovery of cell size and lipid synthesis. The considerable changes in the principal unsaturated fatty acids, 16 : 1 and 18 : 3, which are formed via the palmitate and stearate desaturation pathways, respectively, were suggested to be accounted for by the levels of desaturases activities. The results of the labeling experiments with radioactive precursors have demonstrated that in the refed cells, there was a more rapid and dynamic transfer or exchange between membranes as compared with that in the exponentially growing control cells. Thus, rapid ameliorative modifications of membrane lipid composition are thought to be required for the urgent growth of membrane systems in the refed cell which should be ready to initiate new division.
Animals↗
Regulated covalent modifications of lipid A.
Regulated covalent modifications of lipid A are implicated in virulence of pathogenic Gram-negative bacteria. The Salmonella PhoP/PhoQ-activated gene pagP is required for resistance to cationic antimicrobial peptides and for biosynthesis of hepta-acylated lipid A species containing palmitate. Interestingly, pagP encodes an unusual enzyme of lipid A biosynthesis localized in the outer membrane, whereas all previously characterized lipid A enzymes are cytoplasmic or associated with the inner membrane. PagP is not unique, however, as pagL encodes another outer membrane enzyme in Salmonella that deacylates the 3 position of lipid A.S. typhimurium also synthesizes S-2-hydroxymyristate modified lipid A in a PhoP/PhoQ-dependent manner. We postulated that 2-hydroxylation might be catalyzed by a novel dioxygenase. Using well-characterized dioxygenase sequences as probes, tBLASTn searches revealed unassigned open reading frame(s) with similarity to mammalian aspartyl beta-hydroxylases in bacteria known to make 2-hydroxyacylated lipid A. The S. typhimurium aspartyl beta-hydroxylase homologue (lpxO) was cloned and expressed in Escherichia coli K-12, which does not contain lpxO. Analysis of the resulting construct revealed that lpxO expression induces O(2)-dependent formation of 2-hydroxymyristate-modified lipid A in E. coli. LpxO may be an inner membrane enzyme that catalyzes Fe(2+)/ascorbate/alpha-ketoglutarate dependent hydroxylation of lipid A. We propose that 2-hydroxymyristate released from LPS inside infected animal cells might be converted to 2-hydroxymyristoyl coenzyme A, a potent inhibitor of protein N-myristoyl transferase.
Bacterial Proteins↗
Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ.
Bacterial pathogenesis requires proteins that sense host microenvironments and respond by regulating virulence gene transcription. For Salmonellae, one such regulatory system is PhoP-PhoQ, which regulates genes required for intracellular survival and resistance to cationic peptides. Analysis by mass spectrometry revealed that Salmonella typhimurium PhoP-PhoQ regulated structural modifications of lipid A, the host signaling portion of lipopolysaccharide (LPS), by the addition of aminoarabinose and 2-hydroxymyristate. Structurally modified lipid A altered LPS-mediated expression of the adhesion molecule E-selectin by endothelial cells and tumor necrosis factor-alpha expression by adherent monocytes. Thus, altered responses to environmentally induced lipid A structural modifications may represent a mechanism for bacteria to gain advantage within host tissues.
Acylation↗
Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine.
Wnt signaling pathways regulate many developmental responses; however, little is known about how Wnt ligands function on a biochemical level. Recent studies have shown that Wnt-3a is palmitoylated before secretion. Here we report that Drosophila Wnt-1 (Wingless) also undergoes a lipid modification. Lipidation occurs in the endoplasmic reticulum and is dependent on Porcupine, a putative O-acyltransferase. After modification, DWnt-1 partitions as a membrane-anchored protein and is sorted into lipid raft detergent-insoluble microdomains. Lipidation, raft targeting, and secretion can be blocked by the addition of 2-bromopalmitate, a competitive inhibitor of O-acyltransferase activity. Based on these results we propose a model whereby lipidation targets Wnt-1 to secretory vesicles that deliver the ligand to specialized microdomains at the cell surface where it can be packaged for secretion.
Animals↗
Thematic review series: lipid posttranslational modifications. Lysosomal metabolism of lipid-modified proteins.
Much is now understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins. Central to these pathways are two lysosomal enzymes, palmitoyl-protein thioesterase (PPT1) and prenylcysteine lyase (PCL). PPT1 is a soluble lipase that cleaves fatty acids from cysteine residues in proteins during lysosomal protein degradation. Notably, deficiency in the enzyme causes a neurodegenerative lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis. PCL is a membrane-associated flavin-containing lysosomal monooxygenase that metabolizes prenylcysteine to prenyl aldehyde through a completely novel mechanism. The eventual metabolic fates of other lipidated proteins (such as glycosylphosphatidylinositol-anchored and N-myristoylated proteins) are poorly understood, suggesting directions for future research.
Animals↗
Endogenous ubiquinol prevents protein modification accompanying lipid peroxidation in beef heart submitochondrial particles.
This article is a study of the relationship between lipid peroxidation and protein modification in beef heart submitochondrial particles, and the protective effect of endogenous ubiquinol (reduced coenzyme Q) against these effects. ADP-Fe3+ and ascorbate were used to initiate lipid peroxidation and protein modification, which were monitored by measuring TBARS and protein carbonylation, respectively. Endogenous ubiquinone was reduced by the addition of succinate and antimycin. The parameters investigated included extraction and reincorporation of ubiquinone, and comparison of the effect of ubiquinol with those of various antioxidant compounds and enzymes, as well as the iron chelator EDTA. Under all conditions employed there was a close correlation between lipid peroxidation and protein carbonylation, and the inhibition of these effects by endogenous ubiquinol. SDS-PAGE analysis revealed a differential effect on individual protein components and its prevention by ubiquinol. Conceivable mechanisms behind the observed oxidative modifications of membrane phospholipids and proteins and of the role of ubiquinol in preventing these effects are considered.
Animals↗
Modification of the Ehrlich ascites tumor cell nuclear lipids.
The fatty acid composition of Ehrilich ascites tumor cell nuclei was differend when the tumor-bearing mice were fed diets rich in either coconut or sunflower oil. When coconut oil was fed, the monoenoic fatty acid content of many of the nuclear lipids was increased and their polyenoic fatty acid content was reduced as compared with the sunflower oil diet. By contrast, only small changes were produced in the saturated fatty acid contents of the nuclear lipids. The nuclear membrane choline phospholipid, ethanolamine phospholipid and combined serine phospholipid plus inositol phospholipid fractions exhibited statistically significant changes in fatty acid composition, but the sphingomyelins were not altered appreciably by dietary lipid modification. The fatty acid composition of the small quantity of phospholipids associated with the chromatin was much more resistant to diet-induced mosification. Except for sphingomyelin, the fatty acid composition of the chromatin phospholipids was different from that of the corresponding nuclear membrane phospholipids, containing much larger amounts of fatty acids having less than 16 carbon atoms. The fatty acid compositons of the nuclear triaclglycerols and cholesterol esters, which were associated almost entirely with the chromatin, were modified by the dietary lipid modifications. There were no changes in the DNA, RNA or lipid content of these nuclei. Therefore, this experimental system can be used to prepare mamalian nuclei that differ appreciably only in their fatty acyl composition.
Animals↗
Novel modification of lipid A of Francisella tularensis.
We have investigated the lipid A of Francisella tularensis subsp. holarctica strain 1547-57, a type B strain, by using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, nanoelectrospray quadrupole ion-trap mass spectrometry, and chemical methods. In accordance with the previously published structures of the lipid A from F. tularensis live vaccine strain (LVS) (ATCC 29684) (E. Vinogradov et al., Eur. J. Biochem. 269:6112-6118, 2002), all of the major lipid A forms from strain 1547-57 were tetraacylated. As in the LVS strain, the major fatty acids detected in the F. tularensis 1547-57 lipid A sample included 3-hydroxyoctadecanoic acid, 3-hydroxyhexadecanoic acid, hexadecanoic acid, and tetradecanoic acid. However, several of the lipid A components present in strain 1547-57 were of higher molecular weight than the previously published structures. A major component with an M(r) of 1,666 was found to contain three C(18:0)(3-OH) fatty acids, one C(16:0) fatty acid, one phosphate group, and one 161-Da moiety. This 161-Da moiety could be removed from the lipid A by treatment with aqueous hydrofluoric acid and was identified as galactosamine following peracetylation and analysis by gas chromatography-mass spectrometry. Detailed investigations of the M(r)-1,666 species by ion-trap mass spectrometry with multiple stages of fragmentation suggested that the galactosamine-1-phosphate was linked to the reducing terminus of the lipid A. Similar to the modification of lipid A with arabinosamine, lipopolysaccharide species from F. tularensis containing a phosphate-linked galactosamine could potentially influence its intracellular survival by conferring resistance to antimicrobial peptides.
Francisella tularensis↗
Role of Mg2+ and pH in the modification of Salmonella lipid A after endocytosis by macrophage tumour cells.
Lipid A of Salmonella typhimurium is covalently modified with additional acyl and/or polar substituents in response to activation of the PhoP/PhoQ and/or PmrA/PmrB signalling systems, which are induced by growth at low Mg2+ concentrations and mild acid pH respectively. Although these conditions are thought to exist within macrophage phagolysosomes, no direct evidence for lipid A modification after endocytosis has been presented. To address this issue, we grew S. typhimurium inside RAW264.7 cells in the presence of 32Pi, and then isolated the labelled lipid A fraction, which was found to be extensively derivatized with phosphoethanolamine, aminoarabinose, 2-hydroxymyristate and/or palmitate moieties. S. typhimurium grown in tissue culture medium synthesized lipid A molecules lacking all these substituents with the exception of the 2-hydroxymyristate chain, which was still present. Using defined minimal media to simulate the intracellular pH and Mg2+ concentrations of endosomes, we found that lipid A of S. typhimurium grown in an acidic, low-Mg2+ medium closely resembled lipid A isolated from bacteria internalized by RAW264.7 cells. A subset of S. typhimurium lipid A modifications were induced by low Mg2+ alone. Escherichia coli K-12 W3110 modified its lipid A molecules in response to growth under acidic but not low-Mg2+ conditions. Growth in a high-Mg2+, mildly alkaline medium resulted in suppression of most lipid A modifications with the exception of the 2-hydroxymyristate in S. typhimurium. Although lpxO transcription was stimulated by growth on low Mg2+, the biosynthesis of lipid A species containing 2-hydroxymyristate was independent of PhoP/PhoQ and PmrA/PmrB in S. typhimurium. Our labelling methods should be applicable to studies of lipid A modifications induced by endocytosis of diverse bacteria.
Animals↗
The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica.
The PmrA/PmrB regulatory system of Salmonella enterica controls the modification of lipid A with aminoarabinose and phosphoethanolamine. The aminoarabinose modification is required for resistance to the antibiotic polymyxin B, as mutations of the PmrA-activated pbg operon or ugd gene result in strains that lack aminoarabinose in their lipid A molecules and are more susceptible to polymyxin B. Additional PmrA-regulated genes appear to participate in polymyxin B resistance, as pbgP and ugd mutants are not as sensitive to polymyxin B as a pmrA mutant. Moreover, the role that the phosphoethanolamine modification of lipid A plays in the resistance to polymyxin B has remained unknown. Here we address both of these questions by establishing that the PmrA-activated pmrC gene encodes an inner membrane protein that is required for the incorporation of phosphoethanolamine into lipid A and for polymyxin B resistance. The PmrC protein consists of an N-terminal region with five transmembrane domains followed by a large periplasmic region harboring the putative enzymatic domain. A pbgP pmrC double mutant resembled a pmrA mutant both in its lipid A profile and in its susceptibility to polymyxin B, indicating that the PmrA-dependent modification of lipid A with aminoarabinose and phosphoethanolamine is responsible for PmrA-regulated polymyxin B resistance.
Bacterial Proteins↗
Specific localization and timing in neuronal signal transduction mediated by protein-lipid interactions.
A large number of signaling proteins translocate from the cytosol to the plasma membrane in response to receptor and electrical stimuli. The site of translocation to the plasma membrane and the "on" and "off" rates of the translocation process are critical for defining the specificity of the signaling response. In addition to targeting mechanisms based on protein-protein interactions, signaling proteins have evolved a large repertoire of covalent lipid modifications and lipid binding protein modules that regulate reversible membrane association. The time constants of these membrane interactions range from milliseconds to several hours. Here we discuss how diversity in lipid-based membrane anchoring and targeting motifs contributes to plasticity in neuronal signaling by providing local and regional control mechanisms as well as a means to transduce and integrate signals over a broad range of different time scales.
Amino Acid Sequence↗
S-myristoylation of a glycosylphosphatidylinositol-specific phospholipase C in Trypanosoma brucei.
Covalent modification with lipid can target cytosolic proteins to biological membranes. With intrinsic membrane proteins, the role of acylation can be elusive. Herein, we describe covalent lipid modification of an integral membrane glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC) from the kinetoplastid Trypanosoma brucei. Myristic acid was detected on cysteine residue(s) (i.e. thiomyristoylation). Thiomyristoylation occurred both co- and post-translationally. Acylated GPI-PLC was active against variant surface glycoprotein (VSG). The half-life of fatty acid on GPI-PLC was 45 min, signifying the dynamic nature of the modification. Deacylation in vitro decreased activity of GPI-PLC 18-30-fold. Thioacylation, from kinetic analysis, activated GPI-PLC by accelerating the conversion of a GPI-PLC.VSG complex to product. Reversible thioacylation is a novel mechanism for regulating the activity of a phospholipase C.
Acylation↗
Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm.
Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.
Copper↗
Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the secondary prevention of cardiovascular disease: forecasting the incremental benefits of preventing coronary and cerebrovascular events.
OBJECTIVE: To forecast the long-term benefits and cost-effectiveness of lipid modification in the secondary prevention of cardiovascular disease. METHODS: A validated model based on data from the Lipid Research Clinics cohort was used to estimate the benefits and cost-effectiveness of lipid modification with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) based on results from the Scandinavian Simvastatin Survival Study (4S), including a 35% decrease in low-density-lipoprotein (LDL)-cholesterol levels and an 8% increase in high-density-lipoprotein (HDL)-cholesterol levels. After comparing the short-term outcomes predicted for the 4S with the results actually observed, we forecast the long-term risk of recurrent myocardial infarction, congestive heart failure, transient ischemic attacks, arrhythmias, and strokes and the need for surgical procedures such as coronary artery bypass grafting, catheterization, angioplasty, and pacemaker insertions. Outpatient follow-up care costs were estimated, as were the costs of hospital care and drug therapy. All costs were expressed in 1996 US dollars. RESULTS: The short-term outcomes predicted for the 4S were consistent with the observed results. The long-term benefits of lipid modification among low-risk subjects (normotensive nonsmokers) with a baseline LDL/ HDL ratio of 5 but no other risk factors ranged from $5424 to $9548 per year of life saved for men and $8389 to $13747 per year of life saved for women. In high-risk subjects (hypertensive smokers) with an LDL/HDL ratio of 5, the estimated costs ranged from $4487 to $8532 per year of life saved in men and $5138 to $8389 per year of life saved in women. Assuming that lipid modification has no effect on the risk of stroke, cost-effectiveness increased by as much as 100%. CONCLUSIONS: These long-term cost estimates are consistent with the short-term economic analyses of the published 4S results. The long-term treatment of hyperlipidemia in secondary prevention is forecasted to be cost-effective across a broad range of patients between 40 and 70 years of age. Recognizing the additional effects of lipid changes on cerebrovascular events can substantially improve the cost-effectiveness of treating hyperlipidemia.
Adult↗
Lipid hydroperoxide modification of proteins during myocardial ischaemia.
OBJECTIVE: Lipid hydroperoxides (LOOH) are lipid peroxidation products formed during oxidative stress. A component of their cytotoxicity is mediated by the direct modification of proteins. OBJECTIVES: (i) To assess whether ischaemia and reperfusion in the isolated rat heart generates LOOH-protein (ii) to characterise the extent, time-course and subcellular localization of any protein adducts formed. METHODS: Using a well-characterised antibody which binds to LOOH-modified proteins and densitometry of Western blots, we quantified the amounts of LOOH-protein in control aerobically perfused rat hearts and those subjected to ischaemia with and without reperfusion. RESULTS: Hearts (n=3/4 group), analysed after various periods (0, 5, 10, 20 and 30 min) of zero-flow global ischaemia, exhibited a time-dependent increase in the LOOH-mediated modification of a number of proteins. In hearts subjected to 30 min of ischaemia and then reperfused for various times (0, 5, 10, 20, 30 or 60 min) no changes in LOOH-protein content achieved during the proceeding ischaemic episode were detected. Reperfusion after short periods of ischaemia (5 or 10 min) also did not result in reperfusion-induced LOOH-protein formation. Administration of mercaptopropionylglycine (1 mM) to hearts for 5 min before the onset of 30 min ischaemia efficiently attenuated the formation of LOOH-protein, maintaining the modified proteins at control levels. These Western immunoblot results were confirmed by additional in situ immunofluorescent studies which showed marked LOOH-protein immunostaining in ischaemic tissue around the sarcolemmal membrane. CONCLUSIONS: We conclude that the modification of proteins (particularly those associated with sarcolemmal membranes) by LOOH during ischaemia may contribute to the pathophysiology of ischaemic injury. In addition, these modifications may be initiators of oxidant-induced signal transduction pathways. These findings are consistent with an oxidant stress occurring during ischaemia which is not exacerbated or reduced during the first 60 min of reperfusion.
Animals↗