Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26+/-0.07 poolsday(-1)) relative to controls (n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls (n=70). Cholesterol absorption was 97% of the value for controls (n=15) in the TD subject, at 45%, with cholesterol synthesis and turnover increased modestly by 17 and 25%, respectively. Our data are consistent with the concept that the reductions of LDL observed in TD are due to enhanced catabolism, secondary to changes in LDL composition and size, with neither cholesterol absorption nor metabolism significantly influenced by mutations in ABCA1.
Atherosclerosis 2001 Nov
PMID:Cholesterol and apolipoprotein B metabolism in Tangier disease. 1168 26

The macrophage scavenger receptor CD36 plays an important role in the uptake of oxidized forms of low density lipoprotein (LDL) and contributes to lesion development in murine models of atherosclerosis. However, the structural basis of CD36 lipoprotein ligand recognition is unknown. We now identify a novel class of oxidized phospholipids that serve as high affinity ligands for CD36 and mediate recognition of oxidized forms of LDL by CD36 on macrophages. Small unilamellar vesicles of homogeneous phosphatidylcholine (PC) molecular species were oxidized by the myeloperoxidase (MPO)-H(2)O(2)-NO(2)(-) system, and products were separated by sequential LC/ESI/MS/MS. In parallel, fractions were tested for their ability to bind to CD36. Four major structurally related phospholipids with CD36 binding activity were identified from oxidized 1-palmitoyl-2-arachidonyl-PC, and four corresponding structural analogs with CD36 binding activity were identified from oxidized 1-palmitoyl-2-linoleoyl-PC. Each was then synthetically prepared, its structure confirmed by multinuclear NMR and high resolution mass spectrometry, and shown to possess identical CD36 binding activity and LC/ESI/MS/MS characteristics in both native and derivatized forms. Based upon the structures of the active compounds identified, and structure-function studies with a variety of synthetic analogs, we conclude that the structural characteristics required for high affinity binding of oxidized PC species to CD36 are a phospholipid with an sn-2 acyl group that incorporates a terminal gamma-hydroxy(or oxo)-alpha,beta-unsaturated carbonyl (oxPC(CD36)). LC/ESI/MS/MS studies demonstrate that oxPC(CD36) are formed during LDL oxidation by multiple distinct pathways. Formation of this novel class of oxidized PC species contributes to CD36-mediated recognition of LDL oxidized by MPO and other biologically relevant mechanisms. The present results offer structural insights into the molecular patterns recognized by the scavenger receptor CD36 and provide a platform for the development of potential therapeutic inhibitory agents.
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PMID:Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. 1210 95

High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL, metabolism, yet the evidence has been scarce and conflicting. We have inactivated EL in mice by gene targeting. EL(-/-) mice have elevated plasma and HDL cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an abundance of large HDL particles. There is down-regulation of the transcripts for phospholipid transfer protein, but up-regulation of those for hepatic lipase and lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase activity toward endogenous EL(-/-) substrate is, however, reduced by 50%. HDL clearance is decreased in EL(-/-) mice; both the structure of HDL and the presence of EL are factors that determine the rate of clearance. To determine EL's role in humans, we find a significant association between a single-nucleotide polymorphism 584C/T in the EL (LIPG) gene and HDL cholesterol in a well characterized population of 372 individuals. We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans.
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PMID:Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism. 1260 Nov 78

Oxidized lipoproteins may play an important role in the pathogenesis of atherosclerosis. Elevated levels of 3-chlorotyrosine, a specific end product of the reaction between hypochlorous acid (HOCl) and tyrosine residues of proteins, have been detected in atherosclerotic tissue. Thus, HOCl generated by the phagocyte enzyme myeloperoxidase represents one pathway for protein oxidation in humans. One important target of the myeloperoxidase pathway may be high density lipoprotein (HDL), which mobilizes cholesterol from artery wall cells. To determine whether activated phagocytes preferentially chlorinate specific sites in HDL, we used tandem mass spectrometry (MS/MS) to analyze apolipoprotein A-I that had been oxidized by HOCl. The major site of chlorination was a single tyrosine residue located in one of the protein's YXXK motifs (where X represents a nonreactive amino acid). To investigate the mechanism of chlorination, we exposed synthetic peptides to HOCl. The peptides encompassed the amino acid sequences YKXXY, YXXKY, or YXXXY. MS/MS analysis demonstrated that chlorination of tyrosine in the peptides that contained lysine was regioselective and occurred in high yield if the substrate was KXXY or YXXK. NMR and MS analyses revealed that the N(epsilon) amino group of lysine was initially chlorinated, which suggests that chloramine formation is the first step in tyrosine chlorination. Molecular modeling of the YXXK motif in apolipoprotein A-I demonstrated that these tyrosine and lysine residues are adjacent on the same face of an amphipathic alpha-helix. Our observations suggest that HOCl selectively targets tyrosine residues that are suitably juxtaposed to primary amino groups in proteins. This mechanism might enable phagocytes to efficiently damage proteins when they destroy microbial proteins during infection or damage host tissue during inflammation.
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PMID:Lysine residues direct the chlorination of tyrosines in YXXK motifs of apolipoprotein A-I when hypochlorous acid oxidizes high density lipoprotein. 1466 Jun 78

Recent studies have suggested that ibuprofen inhibits low-density lipoprotein oxidation in a high dose-dependent manner and is a promising drug for treatment of the conditions associated with atherosclerosis. In this article, we present the NMR spectroscopic evidence for the interaction between ibuprofen and phospholipids in lipoprotein particles in intact human plasma. Ibuprofen caused chemical shift upfield drifts for the protons of -N(+)(CH(3))(3) moieties of phosphatidylcholine and sphingomyelin, olefinic chains (-CH[double bond]CH[bond], [bond]CH[triple bond]CHCH(2)CH[triple bond]CH[bond], [bond](CH(2))(n)CH(2)CH[double bond]), and (CH(2))(n) and CH(3) groups, from unsaturated lipids in lipoprotein particles. The ibuprofen may interact directly with the above-mentioned groups of phospholipids or induce structural changes in the lipoproteins. This may shed light on the mechanism by which the drug protects against oxidative modification of lipoproteins.
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PMID:1H NMR spectroscopic evidence of interaction between ibuprofen and lipoproteins in human blood plasma. 1469 Jun 94

Low serum Mg2+ has been associated with an increased incidence of cardiovascular pathology in human populations. We investigated the effect of extracellular Mg2+ on Fe-catalyzed lipid peroxidation in rat aortic segments and in human aortic smooth muscle cells. Products of phospholipid oxidation [malonaldehyde (MDA) and 4-hydroxyalkenals (4-HA)], loss of fatty acyl double bonds (by proton-NMR) and glutathione levels indicated that exogenous ferric ions were several-fold more effective than ferrous ions in causing lipid peroxidation. Increased peroxidation was detectable at <1.0 microM Fe3+. Exogenous ferric iron-ionophore, 8-hydroxyquinoline, did not increase peroxidation by ferric ion, suggesting that Fe-catalyzed lipid peroxidation occurred at the cell surface. As ionized serum [Mg2+](o) was lowered from the physiological (0.7-0.96 mM) into the pathophysiological range (0.3-0.5mM) in Fe3+-containing medium, MDA/4-HA levels increased two to three-fold, with a concomitant loss of fatty acyl double bonds and decreased extracellular glutathione. Conversely, MDA/4-HA decreased as ionized Mg2+ was increased, accompanied by a rise in extracellular glutathione. The results indicate that Mg2+ protects aortic cell plasma membranes from ferric iron-catalyzed lipid peroxidation and that this is a contributing factor in the protective action of ionized Mg2+ on the cardiovascular system.
Atherosclerosis 2004 Jul
PMID:Iron-catalyzed lipid peroxidation in aortic cells in vitro: protective effect of extracellular magnesium. 1518 42

Phenolics from grapes and wines can play a role against oxidation and development of atherosclerosis. Stilbenes have been shown to protect lipoproteins from oxidative damage and to have cancer chemopreventive activity. We describe a method for the direct determination of stilbenes in several red wines using high-performance liquid chromatography with UV detection. In a survey of 12 commercial wines from the south of Brazil (Rio Grande del Sul), levels of delta-viniferin are reported for the first time in different varieties of red wines. Brazilian red wine contains trans-astringin, trans-piceid, trans-resveratrol, cis-resveratrol (in high quantity: 5 times more than the trans form), epsilon-viniferin, and a compound isolated for the first time in wine, trans-delta-viniferin. Isolation and identification of delta-viniferin was achieved by NMR after extraction and fractionation of red wine phenolics. delta-Viniferin contributes, as well as cis-resveratrol and trans-piceid, to a significant proportion of stilbenes in wine dietary intake, particularly with Merlot varieties containing an average level of 10 mg/L for delta-viniferin, 15 mg/L for cis-resveratrol, and 13 mg/L for trans-piceid. The total stilbene intake from wine origin was estimated for the Brazilian population as 5.3 mg/day per person (on the basis of a regular wine consumption of 160 mL/day). delta-Viniferin can contribute to around 20% of total stilbenes in wine (average of 6.4 mg/L in red Brazilian wines). It would be important in the future to investigate the origins of the differences in wine stilbene levels in relation to the vine varieties, and the bioavailability of the newly extracted stilbene delta-viniferin in plasma after consumption of different types of wines.
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PMID:Determination of stilbenes (delta-viniferin, trans-astringin, trans-piceid, cis- and trans-resveratrol, epsilon-viniferin) in Brazilian wines. 1599 30

Class A amphipathic helical peptides have been shown to mimic apolipoprotein A-I, the major protein component of high density lipoproteins and have been shown to inhibit atherosclerosis in several dyslipidemic mouse models. Previously we reported the NMR structure of Ac-18A-NH2, the base-line model class A amphipathic helical peptide in a 50% (v/v) trifluoroethanol-d3/water mixture, a membrane-mimic environment (Mishra, V. K., Palgunachari, M. N., Anantharamaiah, G. M., Jones, M. K., Segrest, J. P., and Krishna, N. R. (2001) Peptides 22, 567-573). The peptide Ac-18A-NH2 forms discoidal nascent high density lipoprotein-like particles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine. Because subtle structural changes in the peptide.lipid complexes have been shown to be responsible for their antiatherogenic properties, we undertook high resolution NMR studies to deduce detailed structure of recombinant peptide.1,2-dimyristoyl-sn-glycero-3-phosphocholine complexes. The peptide adopts a well defined amphipathic alpha helical structure in association with the lipid at a 1:1 peptide:lipid weight ratio. Nuclear Overhauser effect spectroscopy revealed a number of intermolecular close contacts between the aromatic residues in the hydrophobic face of the helix and the lipid acyl chain protons. The pattern of observed peptide-lipid nuclear Overhauser effects is consistent with a parallel orientation of the amphipathic alpha helix, with respect to the plane of the lipid bilayer, on the edge of the disc (the belt model). Based on the results of chemical cross-linking and molecular modeling, we propose that peptide helices are arranged in a head to tail fashion to cover the edge of the disc. This arrangement of peptides is also consistent with the pKa values of the Lys residues determined previously. Taken together, these results provide for the first time a high resolution structural view of the peptide.lipid discoidal complexes formed by a class A amphipathic alpha helical peptide.
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PMID:Association of a model class A (apolipoprotein) amphipathic alpha helical peptide with lipid: high resolution NMR studies of peptide.lipid discoidal complexes. 1640 55

Numerous studies have suggested relationships between myeloperoxidase, inflammation, and atherosclerosis. MPO-derived reactive chlorinating species (RCS) attack membrane plasmalogens releasing alpha-chloro-fatty aldehydes (alpha-Cl-FALDs) including 2-chlorohexadecanal (2-ClHDA). The molecular targets of alpha-Cl-FALDs are not known. The current study demonstrates 2-ClHDA adducts with ethanolamine glycerophospholipids and Fmoc-lysine. Utilizing electrospray ionization mass spectrometry, chlorinated adducts were observed that are apparent Schiff base adducts. Reduction of these Schiff base adducts with sodium cyanoborohydride resulted in a novel, stable adduct produced by the elimination of HCl. NMR further confirmed this structure. 2-ClHDA adducts with ethanolamine glycerophospholipids were also substrates for phospholipase D (PLD). The hydrolysis products were derivatized to pentafluorobenzoyl esters, and further structurally confirmed by GC-MS. Multiple molecular species of 2-ClHDA-N-modified ethanolamine glycerophospholipids were observed in endothelial cells treated with 2-ClHDA. These results show novel Schiff base adducts of alpha-Cl-FALDs with primary amines, which may represent an important fate of alpha-Cl-FALDs.
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PMID:Myeloperoxidase-derived 2-chlorohexadecanal forms Schiff bases with primary amines of ethanolamine glycerophospholipids and lysine. 1641 4

Proton NMR spectroscopy as a means to quantify lipoprotein subclasses has received wide clinical interest. The experimental part is a fast routine procedure that contrasts favourably to other lipoprotein measurement protocols. The difficulties in using (1)H NMR, however, are in uncovering the subclass specific information from the overlapping data. The NMR-based quantification has been evaluated only in relation to biochemical measures, thereby leaving the inherent capability of NMR rather vague due to biological variation and diversity among the biochemical experiments. Here we will assess the use of (1)H NMR spectroscopy of plasma per se. This necessitates data for which the inherent parameters, namely the shapes and areas of the (1)H NMR signals of the subclasses are available. This was achieved through isolation and (1)H NMR experiments of 11 subclasses--VLDL1, VLDL2, IDL, LDL1, LDL2, LDL3, HDL(2b), HDL(2a), HDL(3a), HDL(3b) and HDL(3c)--and the subsequent modelling of the spectra. The subclass models were used to simulate biochemically representative sets of spectra with known subclass concentrations. The spectral analyses revealed 10-fold differences in the quantification accuracy of different subclasses by (1)H NMR. This finding has critical significance since the usage of (1)H NMR methodology in the clinical arena is rapidly increasing.
Atherosclerosis 2007 Feb
PMID:The inherent accuracy of 1H NMR spectroscopy to quantify plasma lipoproteins is subclass dependent. 1673 Jul 30


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