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)

Hypochlorous acid (HOCl), generated by myeloperoxidase released from activated macrophages, is thought to contribute to vascular dysfunction and oxidation of low density lipoproteins (LDLs) in atherogenesis. We have previously shown that HOCl exposure can cause chlorination and oxidation of isolated DNA and that vitamin C protects human arterial smooth muscle cells against oxidized LDL-mediated damage. We report in the present study that vitamin C attenuates HOCl-induced DNA base and protein damage and depletion of intracellular glutathione (GSH) and ATP in human arterial smooth muscle cells. Cells were pretreated in the absence or presence of 100 micromol/L vitamin C (24 hours) and then exposed to HOCl (0 to 500 micromol/L, 0 to 60 minutes) in the absence of vitamin C. Intracellular GSH and ATP levels were depleted by HOCl treatment, and gas chromatography-mass spectroscopy revealed a concentration- and time-dependent increase in DNA base oxidation and protein damage (measured as 3-chlorotyrosine). Pretreatment of smooth muscle cells with vitamin C significantly reduced the extent of HOCl-induced DNA and protein damage and attenuated decreases in intracellular ATP and GSH. Our findings suggest that physiological levels of vitamin C provide an important antioxidant defense against HOCl-mediated injury in atherosclerosis.
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PMID:Vitamin C protects against hypochlorous Acid-induced glutathione depletion and DNA base and protein damage in human vascular smooth muscle cells. 1195 Jun 93

Dietary polyphenolics such as those in soy or red wine can have beneficial effects on the development of chronic human diseases. The mechanisms of action of isoflavones have been diverse and include their roles as weak estrogens, inhibitors of tyrosine kinase-dependent signal transduction processes and as antioxidants. Recent insights into the oxidative stress model of atherosclerosis suggest an interesting synthesis of these concepts. Sites of inflammation are associated with the formation of complex mixtures of reactive oxygen, nitrogen and halogenating species capable of modifying both endogenous biomolecules and polyphenolics. Of particular significance are the halogenation reactions mediated by myeloperoxidase that can modify key amino acids such as arginine and polyphenolics such as genistein. Hypochlorite, the reaction product of myeloperoxidase can halogenate polyphenolics to form stable derivatives with modified biological activity. Thus the in situ metabolism at sites of inflammation is unique and generates novel pharmacophores with potentially distinct modes of action from the parent compounds.
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PMID:Formation of novel bioactive metabolites from the reactions of pro-inflammatory oxidants with polyphenolics. 1201 30

Oxidatively modified low-density lipoprotein (LDL) has been strongly implicated in the pathogenesis of atherosclerosis. Peripheral blood leukocytes, such as neutrophils, can oxidize LDL by processes requiring superoxide and redox-active transition metal ions; however, it is uncertain whether such catalytic metal ions are available in the artery wall. Stimulated leukocytes also produce the reactive oxidant hypochlorous acid (HOCl) via the heme enzyme myeloperoxidase. Since myeloperoxidase-derived HOCl may be a physiologically relevant oxidant in atherogenesis, we investigated the mechanisms of neutrophil-mediated LDL modification and its possible prevention by the antioxidant ascorbate (vitamin C). As a sensitive marker of LDL oxidation, we measured LDL thiol groups. Stimulated human neutrophils (5x10(6) cells/ml) incubated with human LDL (0.25 mg protein/ml) time-dependently oxidized LDL thiols (33% and 79% oxidized after 10 and 30 min, respectively). Supernatants from stimulated neutrophils also oxidized LDL thiols (33% oxidized after 30 min), implicating long-lived oxidants such as N-chloramines. Experiments using specific enzyme inhibitors and oxidant scavengers showed that HOCl, but not hydrogen peroxide nor superoxide, plays a critical role in LDL thiol oxidation by neutrophils. Ascorbate (200 microM) protected against neutrophil-mediated LDL thiol oxidation for up to 15 min of incubation, after which LDL thiols became rapidly oxidized. Although stimulated neutrophils accumulated ascorbate during oxidation of LDL, pre-loading of neutrophils with ascorbate did not attenuate oxidant production by the cells. Thus, activated neutrophils oxidize LDL thiols by HOCl- and N-chloramine-dependent mechanisms and physiological concentrations of vitamin C delay this process, most likely due to scavenging of extracellular oxidants, rather than by attenuating neutrophil oxidant production.
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PMID:Human neutrophils oxidize low-density lipoprotein by a hypochlorous acid-dependent mechanism: the role of vitamin C. 1203 52

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

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.
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PMID:Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. 1221 35

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
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PMID:Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers. 1235 48

Oxidation is believed to play a role in atherosclerosis. Oxidized lipids, sterols and proteins have been detected in early, intermediate and advanced human lesions at elevated levels. The spectrum of oxidized side-chain products detected on proteins from homogenates of advanced human lesions has been interpreted in terms of the occurrence of two oxidative mechanisms, one involving oxygen-derived radicals catalysed by trace transition metal ions, and a second involving chlorinating species (HOCl or Cl2), generated by the haem enzyme myeloperoxidase (MPO). As MPO is released extracellularly by activated monocytes (and possibly macrophages) and is a highly basic protein, it would be expected to associate with polyanions such as the glycosaminoglycans of the extracellular matrix, and might result in damage being localized at such sites. In this study proteins extracted from extracellular matrix material obtained from advanced human atherosclerotic lesions are shown to contain elevated levels of oxidized amino acids [3,4-dihydroxyphenylalanine (DOPA), di-tyrosine, 2-hydroxyphenylalanine ( o-Tyr)] when compared with healthy (human and pig) arterial tissue. These matrix-derived materials account for 83-96% of the total oxidized protein side-chain products detected in these plaques. Oxidation of matrix components extracted from healthy artery tissue, and model proteins, with reagent HOCl is shown to give rise to a similar pattern of products to those detected in advanced human lesions. The detection of elevated levels of DOPA and o-Tyr, which have been previously attributed to the occurrence of oxygen-radical-mediated reactions, by HOCl treatment, suggests an alternative route to the formation of these materials in plaques. This is believed to involve the formation and subsequent decomposition of protein chloramines.
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PMID:Detection of HOCl-mediated protein oxidation products in the extracellular matrix of human atherosclerotic plaques. 1245 64

1. Reactive oxygen species (ROS) are known to be involved in the progression of various cardiovascular diseases. One source of ROS is activated neutrophils, which can release superoxide anion radicals and hydrogen peroxide by membrane-bound NAD(P)H oxidases. These ROS not only destroy bacteria, but may also affect mammalian tissue. In addition, hydrogen peroxide serves as a substrate for myeloperoxidase, an enzyme that is released by activated neutrophils during inflammatory processes, as seen, for instance, in reperfusion injury and atherosclerosis. Myeloperoxidase catalyses the oxidation of chloride by hydrogen peroxide, yielding hypochlorite, an extremely potent oxidant. 2. The purpose of the present study was to evaluate the effects of hypochlorite on a variety of receptor-dependent processes in rat isolated left atria and rat thoracic aorta and to compare these results with the phenomena observed after incubation with hydrogen peroxide. 3. In the presence of hypochlorite (300 micro mol/L), the positive inotropic response of alpha1-adrenoceptor stimulation by methoxamine (300 micro mol/L) was converted into a negative inotropic response. In contrast, the positive inotropic effects of the beta1/beta2-adrenoceptor agonist isoprenaline (3 micro mol/L) and endothelin (ET)-1 (100 nmol/L) remained largely unaffected. 4. The inversion of alpha1-adrenoceptor-mediated inotropy was not obtained in the presence of hydrogen peroxide (500 micro mol/L). Hydrogen peroxide did not affect the positive inotropic response of isoprenaline, but it completely abolished the inotropic effect of ET-1. 5. The effect of cardiac M2-receptor stimulation was studied in the presence of hypochlorite and hydrogen peroxide. The negative inotropic response to acetylcholine (ACh) was significantly enhanced after hypochlorite incubation compared with control. 6. In the rat thoracic aorta, endothelial function, evaluated by means of ACh-induced vasodilation, was completely abolished in the presence of hypochlorite (100 micro mol/L), but remained unaffected by treatment with the same concentration of hydrogen peroxide. 7. From these data, we conclude that hypochlorite exerts more toxic properties than its precursor hydrogen peroxide, leading to substantial physiological alterations in cardiac and vascular tissue.
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PMID:Effects of hypochlorite and hydrogen peroxide on cardiac autonomic receptors and vascular endothelial function. 1268 Aug 42

Neutrophil-endothelial adhesion is a crucial step in vascular inflammation, which is recognized as the direct cause of atherosclerosis-mediated serious diseases. We demonstrated previously that high glucose increased adhesion in a protein kinase C (PKC)-dependent manner within 48 h through increasing surface expression of endothelial adhesion molecules. On the other hand, statins, used for patients with hypercholesterolemia, have been shown to decrease the incidence of atherosclerosis-mediated diseases, but direct effects of statins on endothelial cells remain unclear. In this study, we examined the effects of these compounds on high glucose-mediated neutrophil-endothelial adhesion with respect to the participation of PKC and nitric oxide (NO). After human endothelial cells were cultured for 48 h in high glucose medium, neutrophils from healthy volunteers were added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring their myeloperoxidase activities, and surface expression of endothelial adhesion molecules was determined with an enzyme immunoassay. Both pravastatin (0.05 microM) and fluvastatin (0.5 microM) significantly attenuated the adhesion mediated by 27.8 mM glucose for 48 h through decreasing surface expression of endothelial adhesion molecules (intercellular adhesion molecule-1, P-selectin, and E-selectin). NO synthase inhibitors reduced the inhibitory effects of statins, whereas statins did not affect the adhesion mediated by a PKC activator. These data suggest that statins act directly on endothelial cells to inhibit expression of adhesion molecules and neutrophil adhesion mediated by high glucose through increasing endothelial NO production, but not by inhibiting PKC.
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PMID:Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide. 1268 69

Oxidative stress has been implicated in the cardiovascular complications in chronic renal failure patients. Lipoprotein oxidation is involved in the genesis of atherosclerosis. Both the lipid and the protein moieties of low-density lipoproteins (LDL) are subject to oxidation. We have shown that oxidation of LDL by hypochlorous acid (HOCl) in vitro, reflecting increased myeloperoxidase (MPO) activity in vivo, leads mainly to modifications of apolipoproteins, such that the latter in turn induce high rates of apoptosis in a human monocytic cell line via a caspase-dependent pathway. These in vitro oxidative changes of LDL protein moiety, if shown to occur to a significant extent in uremic patients in vivo, may represent an important pathway in the pathogenesis of atherogenesis.
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PMID:New insights into the effects of the protein moiety of oxidized LDL (oxLDL). 1269 26


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