Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Scavenger receptors mediate the endocytosis of chemically modified lipoproteins, such as acetylated low density lipoprotein (Ac-LDL) and oxidized LDL (Ox-LDL), and have been implicated in the pathogenesis of atherosclerosis. The evidence that endothelial cells possess scavenger receptor activity is substantial, and this property is widely used in the isolation of endothelial cells from vascular tissues. In the current study, we have isolated, by expression cloning, the cDNA encoding a novel type of scavenger receptor expressed by endothelial cells (SREC), which mediates the binding and degradation of Ac-LDL. The primary structure of the molecule has no significant homology to other types of scavenger receptors, including the recently cloned endothelial cell Ox-LDL receptor, a member of the C-type lectin family. The cDNA encodes a protein of 830 amino acids with a calculated molecular mass of 85, 735 Da (mature peptide). Chinese hamster ovary cells stably expressing SREC bound 125I-labeled Ac-LDL with high affinity (Kd = 3.0 microg/ml, approximately 1.7 nM) and degraded them via an endocytic pathway. Association of DiII-Ac-LDL were effectively inhibited by Ox-LDL, malondialdehyde-modified LDL, dextran sulfate, and polyinosinic acid, but not by natural LDL and heparin. The cloned receptor has several characteristic domain structures, including an N-terminal extracellular domain with five epidermal growth factor-like cysteine pattern signatures and an unusually long C-terminal cytoplasmic domain (391 amino acids) composed of a Ser/Pro-rich region followed by a Gly-rich region.
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PMID:Expression cloning of a novel scavenger receptor from human endothelial cells. 939 44

The effective action of endothelium-derived nitric oxide (EDNO) is impaired in patients with atherosclerosis. This impairment has been attributed in part to increased vascular oxidative stress. EDNO action is improved by administration of ascorbic acid, a water-soluble antioxidant. Ascorbic acid is a potent free-radical scavenger in plasma, and also regulates intracellular redox state in part by sparing cellular glutathione. We specifically investigated the role of intracellular redox state in EDNO action by examining the effect of L-2-oxo-4-thiazolidine carboxylate (OTC) on EDNO-dependent, flow-mediated dilation in a randomized double-blind placebo-controlled study of patients with angiographically proven coronary artery disease. OTC augments intracellular glutathione by providing substrate cysteine for glutathione synthesis. Brachial artery flow-mediated dilation was examined with high-resolution ultrasound before and after oral administration of 4.5 g of OTC or placebo in 48 subjects with angiographically documented coronary artery disease. Placebo treatment produced no change in flow-mediated dilation (7.0+/-3.9% vs. 7.2+/-3.7%), whereas OTC treatment was associated with a significant improvement in flow-mediated dilation (6.6+/-4.4% vs. 11.0+/-6.3%; P = 0.005). OTC had no effect on arterial dilation to nitroglycerin, systemic blood pressure, heart rate, or reactive hyperemia. These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.
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PMID:L-2-Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease. 950 83

Oxygen radical injury and lipid peroxidation have been suggested as major causes of cancer, atherosclerosis and the aging process. We examined in vitro the effect of garlic on H2O2-induced oxidant injury in bovine pulmonary artery endothelial cells (PAEC). After overnight preincubation with Aged Garlic Extract (AGE, from Wakunaga Pharmaceutical Co., Ltd., Japan) or S-allyl cysteine (SAC), PAEC monolayers were exposed to H2O2 for 3 h. Cell viability (MTT assay), lactate dehydrogenase (LDH) release, and lipid peroxidation (TBA-RS) were measured to assess oxidant injury. AGE (1-4 mg/ml) pretreatment significantly reduced the loss of cell viability induced by 50-100 microM of H2O2. AGE and SAC exhibited dose dependent inhibition of both LDH release and TBA-RS production induced by 50 microM of H2O2. The results show that AGE and SAC can protect vascular endothelial cells from oxidant injury. Numerous garlic compounds could be involved in the antioxidant properties of garlic, while there could be some prooxidant compounds derived from garlic. It is important to keep an array of antioxidant compounds to develop good herbal preparation, like AGE.
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PMID:[Garlic compounds protect vascular endothelial cells from oxidant injury]. 950 21

Homocysteine can be viewed as the first risk factor for atherosclerosis, believed to exert its effects through a mechanism involving oxidative damage. Oxygen radicals are known to interact with a variety of macromolecules leading to lipid peroxidation, DNA strand breakage and a variety of changes in proteins, including thiol oxidation. The present study deals with the protein-binding of homocysteine, cysteine and glutathione in a human cell line culture exposed to homocysteine and copper ions in order to elucidate the possible role of homocysteine in cell injury and atherogenesis. It is shown that homocysteine has the highest tendency of the thiols investigated to create disulfide bonds with proteins. The interaction with the protein cysteine thiol groups, which are involved in the function of many enzymes, structural proteins and receptors might disturb many metabolic functions in the cell. This finding might therefore be one reason for the cell-damaging effects of homocysteine. Addition of reduced homocysteine to cell cultures decreased the intra- and extracellular proportions of protein-bound thiols except that of intracellular glutathione. In agreement with the pro-oxidative effects of copper ions, the findings in the present study showed an increase of the protein-bound fractions of all thiols after the addition of copper ions. Another finding is that increased (in the presence of 100 mumol/l of copper ions) or decreased (in the presence of 100-2000 mumol/l of homocysteine) proportions of protein-bound fractions of the thiols in these short-term experiments did not seriously affect the cells since the cell growth was unchanged.
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PMID:Protein binding of homocysteine and other thiols in HeLa cell cultures after addition of homocysteine and copper ions. 952 76

Connective Tissue Growth Factor (CTGF) is a cysteine-rich peptide involved in human atherosclerosis and fibrotic disorders such as scleroderma. CTGF has considerable N-terminal sequence similarity with the insulin-like growth factor binding proteins (IGFBPs), including preservation of cysteines, and has been postulated to be a member of the IGFBP superfamily. Indeed, recent studies have shown that baculovirus generated CTGF, a secreted 38-kDa protein, binds IGFs in a specific manner, leading to the provisional renaming of CTGF as IGFBP-8 (or IGFBP-rP2). With immunoprecipitation and immunoblotting, using polyclonal anti-IGFBP-rP2 antibody generated against recombinant human IGFBP-rP2bac, IGFBP-rP2 can be identified in the serum-free conditioned media of Hs578T human breast cancer cells, as well as in various human biological fluids, such as normal sera, pregnancy sera, and cerebrospinal, amniotic, follicular and peritoneal fluids. Glycosylation studies with endoglycosidase F reveal that endogenous human IGFBP-rP2 is a secreted, glycosylated, approximately 32-38-kDa protein with 2-8-kDa of N-linked sugars and a 30-kDa core. There are 18- and 24-kDa proteins that appear to be IGFBP-rP2 degradation products. In Hs578T human breast cancer cells, transforming growth factor (TGF)-beta 2, a potent growth inhibitor for these cells, upregulates IGFBP-rP2 mRNA and protein levels. Expression of Hs578T IGFBP-rP2 is significantly increased by TGF-beta 2 treatment in a dose-dependent manner, with 2.5- and 6-fold increases in mRNA and protein levels, respectively, at a TGF-beta 2 concentration of 10 ng/ml. Our studies indicate that IGFBP-rP2 appears to be an important endocrine factor, and one of the critical downstream effectors of the critical downstream effectors of TGF-beta, similar to the role of IGFBP-3 in TGF-beta-induced growth inhibition in human breast cancer cells.
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PMID:Identification of glycosylated 38-kDa connective tissue growth factor (IGFBP-related protein 2) and proteolytic fragments in human biological fluids, and up-regulation of IGFBP-rP2 expression by TGF-beta in Hs578T human breast cancer cells. 966 51

Homocysteine is a metabolite of methionine that may be remethylated by enzymes requiring folate and cobalamin (vitamin B12) to again form methionine or catabolized by the pyridoxine (vitamin B6) dependent enzyme, cystathionine beta synthase (CBS) to form cysteine (fig. 1) [1]. Homocysteine exists as a combination of various free and protein bound forms, but the total amount is what is usually measured and may be reported as homocyst(e)ine [2]. The biological plausibility that elevated homocysteine might lead to vascular disease noted in 1969 by McCully [3]. He reported that a child with abnormal cobalamin metabolism and hyperhomocysteinemia had arterial lesions similar to those seen in children with severe hyperhomocysteinemia from CBS deficiency. These findings led to the idea that moderate elevations in homocysteine, even those still within the so-called normal range, might also lead to vascular pathology through a variety of mechanisms including atherosclerosis and thrombosis [4].
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PMID:Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. 970 30

Low concentrations of serum or interstitial fluid have been shown to inhibit the oxidation of low density lipoprotein (LDL) catalysed by copper or iron, and may therefore protect against the development of atherosclerosis. As atherosclerotic lesions may have an acidic extracellular pH, we have investigated the effect of pH on the inhibition of LDL oxidation by serum and certain components of serum. Human serum (0.5%, v/v), lipoprotein-deficient human serum at an equivalent concentration and the amino acids L-cysteine (25 microM) and L-histidine (25 microM), but not L-alanine (25 microM), inhibited effectively the oxidation of LDL by copper at pH 7.4, as measured by the formation of conjugated dienes. The antioxidant protection was reduced considerably at pH 6.5, and was decreased further at pH 6.0. These observations may help to explain why LDL becomes oxidised locally in atherosclerotic lesions in the presence of the strong antioxidant protection offered by extracellular fluid.
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PMID:Human serum, cysteine and histidine inhibit the oxidation of low density lipoprotein less at acidic pH. 974 46

The mutant form of human apoA1, known as apoA1 Milano, is formed as a result of arginine 173 to cysteine substitution and inhibits experimental atherosclerosis in cholesterol-fed animals. This study was designed to determine if apoA1 Milano would modify arterial thrombogenesis. Sprague Dawley rats were intravenously administered the carrier alone (n=8) or apoA1 Milano (20 mg. kg-1. d-1 for 4 to 10 days, n=17). The abdominal cavity was opened, and the abdominal aorta was isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was recorded continuously. In carrier-treated rats, an occlusive platelet-fibrin-rich thrombus was formed in 21.2+/-4.1 (mean+/-SD) minutes. Treatment of rats with apoA1 Milano markedly delayed time to thrombus formation (38.8+/-11.9 versus 21.2+/-4.1 minutes, P<0. 01), inhibited platelet aggregation (25+/-7% versus 50+/-11%, P<0. 01), and reduced weight of the thrombus (18.5+/-1.8 versus 23.7+/-2. 3 mg/cm, P<0.01). Total cholesterol and HDL levels remained similar in both groups of rats, but plasma apoA1 Milano levels were elevated in apoA1 Milano-treated rats. In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis.
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PMID:Inhibition of arterial thrombus formation by ApoA1 Milano. 997 22

The oxidation of low density lipoproteins (LDL) has been implicated in the development of atherosclerosis. Recently, we found that polar lipids isolated from minimally oxidized LDL produced a dramatic inhibition of lecithin: cholesterol acyltransferase (LCAT) activity, suggesting that HDL-cholesterol transport may be impaired during early atherogenesis. In this study, we have identified molecular species of oxidized lipids that are potent inhibitors of LCAT activity. Treatment of LDL with soybean lipoxygenase generated small quantities of lipid hydroperoxides (20 +/- 4 nmol/mg LDL protein, n = 3); but when lipoxygenase-treated LDL (1 mg protein/ml) was recombined with the d > 1.063 g/ml fraction of human plasma, LCAT activity was rapidly inhibited (25 +/- 4 and 65 +/- 16% reductions by 1 and 3 h, respectively). As phospholipid hydroperoxides (PL-OOH) are the principal oxidation products associated with lipoxygenase-treated LDL, we directly tested whether PL-OOH inhibited plasma LCAT activity. Detailed dose-response curves revealed that as little as 0.2 and 1.0 mole % enrichment of plasma with PL-OOH produced 20 and 50% reductions in LCAT activity by 2 h, respectively. To gain insight into the mechanism of LCAT impairment, the enzyme's free cysteines (Cys31 and Cys184) and active site residues were "capped" with the reversible sulfhydryl compound, DTNB, during exposure to either minimally oxidized LDL or PL-OOH. Reversal of the DTNB "cap" after such exposures revealed that the enzyme was completely protected from both sources of peroxidized phospholipids. We, therefore, conclude that PL-OOH inhibited plasma LCAT activity by modifying the enzyme's free cysteine and/or catalytic residues. These studies are the first to suggest that PL-OOH may accelerate the atherogenic process by impairing LCAT activity.
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PMID:Evidence that lipid hydroperoxides inhibit plasma lecithin:cholesterol acyltransferase activity. 1022 64

Human serum paraoxonase (PON1) can protect low density lipoprotein (LDL) from oxidation induced by either copper ion or by the free radical generator azo bis amidinopropane hydrochloride (AAPH). During LDL oxidation in both of these systems, a time-dependent inactivation of PON arylesterase activity was observed. Oxidized LDL (Ox-LDL) produced by lipoprotein incubation with either copper ion or with AAPH, indeed inactivated PON arylesterase activity by up to 47% or 58%, respectively. Three possible mechanisms for PON inactivation during LDL oxidation were considered and investigated: copper ion binding to PON, free radical attack on PON, and/or the effect of lipoprotein-associated peroxides on the enzyme. As both residual copper ion and AAPH are present in the Ox-LDL preparations and could independently inactivate the enzyme, the effect of minimally oxidized (Ox-LDL produced by LDL storage in the air) on PON activity was also examined. Oxidized LDL, as well as oxidized palmitoyl arachidonoyl phosphatidylcholine (PAPC), lysophosphatidylcholine (LPC, which is produced during LDL oxidation by phospholipase A2-like activity), and oxidized cholesteryl arachidonate (Ox-CA), were all potent inactivators of PON arylesterase activity (PON activity was inhibited by 35%-61%). PON treatment with Ox-LDL (but not with native LDL), or with oxidized lipids, inhibited its arylesterase activity and also reduced the ability of the enzyme to protect LDL against oxidation. PON Arylesterase activity however was not inhibited when PON was pretreated with the sulfhydryl blocking agent, p-hydroxymercurybenzoate (PHMB). Similarly, on using recombinant PON in which the enzyme's only free sulfhydryl group at the position of cysteine-284 was mutated, no inactivation of the enzyme arylesterase activity by Ox-LDL could be shown. These results suggest that Ox-LDL inactivation of PON involves the interaction of oxidized lipids in Ox-LDL with the PON's free sulfhydryl group. Antioxidants such as the flavonoids glabridin or quercetin, when present during LDL oxidation in the presence of PON, reduced the amount of lipoprotein-associated lipid peroxides and preserved PON activities, including its ability to hydrolyze Ox-LDL cholesteryl linoleate hydroperoxides. We conclude that PON's ability to protect LDL against oxidation is accompanied by inactivation of the enzyme. PON inactivation results from an interaction between the enzyme free sulfhydryl group and oxidized lipids such as oxidized phospholipids, oxidized cholesteryl ester or lysophosphatidylcholine, which are formed during LDL oxidation. The action of antioxidants and PON on LDL during its oxidation can be of special benefit against atherosclerosis since these agents reduce the accumulation of Ox-LDL by a dual effect: i.e. prevention of its formation, and removal of Ox-LDL associated oxidized lipids which are generated during LDL oxidation.
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PMID:Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. 1023 33


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