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)

In order to identify potential atherogenic properties of gas-phase cigarette smoke, we utilized an in vitro exposure model to determine whether the activities of several putative anti-atherogenic enzymes associated with plasma lipoproteins were compromised. Exposure of heparinized human plasma to gas-phase cigarette smoke produced a dose-dependent reduction in the activity of platelet-activating factor acetylhydrolase (PAF-AH). Reductions of nearly 50% in PAF-AH activity were observed following exposure to gas-phase smoke from four cigarettes over an 8-h period. During this time of exposure, lecithin:cholesterol acyltransferase (LCAT) was rendered almost completely inactive (>80%). In contrast, paraoxonase was totally unaffected by cigarette smoke. Supplementation of plasma with 1 mM reduced glutathione was found to protect both PAF-AH and LCAT from cigarette smoke, suggesting that cysteine modifications may have contributed to the inhibition of these two enzymes. To evaluate this possibility, we blocked the free cysteine residues of these enzymes with the reversible thiol-modifying reagent dithiobisnitrobenzoic acid (DTNB). Reversal of the DTNB-cysteine adducts following cigarette smoke exposures revealed that LCAT, but not PAF-AH, was protected. Moreover, high doses (1.0-10 mM) of acrolein and 4-hydroxynonenal, reactive aldehydic species associated with cigarette smoke, completely inhibited plasma LCAT activity, whereas PAF-AH was resistant to such exposures. Taken together, these results indicate a divergence regarding the underlying mechanism of PAF-AH and LCAT inhibition upon exposure to gas-phase cigarette smoke. While LCAT was sensitive to exposure to volatile aldehydic products involving, in part, cysteine and/or active site modifications, the enzyme PAF-AH exhibited an apparent resistance. The latter suggests that the active site of PAF-AH is in a microenvironment that lacks free cysteine residues and/or is shielded from volatile aldehydic combustion products. Based on these results, we propose that cigarette smoke may contribute to atherogenesis by inhibiting the activities of plasma PAF-AH and LCAT, but the nature of this inhibition differs for the enzymes.
Atherosclerosis 2001 Mar
PMID:Relative sensitivities of plasma lecithin:cholesterol acyltransferase, platelet-activating factor acetylhydrolase, and paraoxonase to in vitro gas-phase cigarette smoke exposure. 1122 28

The effects of vegetable seed oil on hyperlipidemia induced by high lipid diet in rats. Male adult Wistar rats were fed on the test diet containing 94% high lipid diet and 6% lard pinon seed oil, perilla seed oil, blackcurrent seed oil, borage seed oil and evening primrose seed oil respectively for 3 weeks. The results showed that the vale of trilyceride(TG), total cholesterol(TC), low density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C(high density lipoprotein cholesterol) ratio increased and the vale of HDL-C/TC ratio and lecithin-cholesterol acyltransferase(LCAT) activity decreased in the groups with vegetable seed oil were less than that of the control group. The results suggested that all the five kinds of vegetable seed oil had the effect of regulating lipid metabolism of hyperlipidemia rats to some extent. Pinon seed oil and borage seed oil may be well suited for the prevention of atherosclerosis.
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PMID:[Effect of five kinds of vegetable seed oil on serum lipid and lipid peroxidation in rats]. 1125 65

The goal of the present review consists on the relationship between inflammatory disorders, such as that represented by systemic granulomatous diseases like sarcoidosis, and the cholesterol metabolism and its implication in the atherosclerosis process. Serum amyloid A is an acute phase reactant that transiently binds to the high density lipoproteins during an inflammatory response. Serum amyloid A may act either displacing apo A-I, which in turn result in increased catabolism of high density lipoproteins, or inhibiting lecithin-cholesterol acyltransferase activity which leads to low levels of esterified serum cholesterol. This lipoprotein alteration together with a direct effect of the serum amyloid A on the endothelium of the atheromatous plaque suggest a potential pathophysiological link between the inflammatory responses expressed by the serum concentrations of amyloid A and the development of the atherosclerotic process.
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PMID:[Inflammatory response, cholesterol metabolism, and arteriosclerosis]. 1132 88

Human lecithin:cholesterol acyltransferase (LCAT) plays a key role in the biogenesis of circulating high-density lipoprotein-cholesterol (HDL-C) and reverse cholesterol efflux. We investigated the molecular defect in the LCAT gene in a family with low levels of HDL-C. The proband, a 53-year-old woman from Oklahoma City, had a HDL-C level of 0.21 mmol/l. The LCAT activity in the proband was 5 nmol/ml/h and cholesterol esterification rate was 54.2 nmol/ml/h, consistent with LCAT deficiency. Analysis of polymerase chain reaction (PCR) amplified subgenomic fragments of LCAT DNA on polyacrylamide gels revealed heteroduplex bands in the proband and three other affected individuals in exon 6. DNA sequence analyses of the proband's LCAT gene identified a 2 base pair deletion (TC) (base pairs 4544-4545, corresponding to amino acid 255) in the heteroduplex allele, thereby converting Pro(260) to a premature stop codon and a predicted truncated protein of 260 amino acids. This is approximately 60% of the length of the normal translated protein. The heterozygous individuals also revealed significant reduction in apolipoprotein A-1 levels compared with the unaffected family members (n=4). The marked reduction in HDL-C in the proband and sibling suggests a dominant effect of this mutation on HDL-C levels. Furthermore, because the deletion results in a heterozygous allele that can be detected by a simple PCR reaction and polyacrylamide gel-size fractionation, it may be possible to rapidly screen susceptible individuals for the presence of this mutation.
Atherosclerosis 2001 May
PMID:A novel TC deletion resulting in Pro(260)-->Stop in the human LCAT gene is associated with a dominant effect on HDL-cholesterol. 1136 5

Modification of low density lipoprotein (LDL) by myeloperoxidase-generated HOCl has been implicated in human atherosclerosis. Incubation of LDL with HOCl generates several reactive intermediates, primarily N-chloramines, which may react with other biomolecules. In this study, we investigated the effects of HOCl-modified LDL on the activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for high density lipoprotein maturation and the antiatherogenic reverse cholesterol transport pathway. We exposed human LDL (0.5 mg protein/mL) to physiological concentrations of HOCl (25 to 200 micromol/L) and characterized the resulting LDL modifications to apolipoprotein B and lipids; the modified LDL was subsequently incubated with apolipoprotein B-depleted plasma (density >1.063 g/mL fraction), which contains functional LCAT. Increasing concentrations of HOCl caused various modifications to LDL, primarily, loss of lysine residues and increases in N-chloramines and electrophoretic mobility, whereas lipid hydroperoxides were only minor products. LCAT activity was extremely sensitive to HOCl-modified LDL and was reduced by 23% and 93% by LDL preincubated with 25 and 100 micromol/L HOCl, respectively. Addition of 200 micromol/L ascorbate or N-acetyl derivatives of cysteine or methionine completely prevented LCAT inactivation by LDL preincubated with </=200 micromol/L HOCl. Protecting the free thiol groups of LCAT with 5,5'-dithio-bis-(2-nitrobenzoic acid) before exposure to HOCl-modified LDL, which inhibits lipid hydroperoxide-mediated inactivation of LCAT, failed to prevent the loss of enzyme activity. Our data indicate that N-chloramines from HOCl-modified LDL mediate the loss of plasma LCAT activity and provide a novel mechanism by which myeloperoxidase-generated HOCl may promote atherogenesis.
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PMID:Ldl modified by hypochlorous acid is a potent inhibitor of lecithin-cholesterol acyltransferase activity. 1139 17

We have recently shown that a class A amphipathic peptide 5F with increased amphipathicity protected mice from diet-induced atherosclerosis (Garber et al. J. Lipid Res. 2001. 42: 545-552). We have now examined the effects of increasing the hydrophobicity of a series of homologous class A amphipathic peptides, including 5F, on physical and functional properties related to atherosclerosis inhibition by systematically replacing existing nonpolar amino acids with phenylalanine. The peptides, based on the sequence Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH(2) (Ac-18A-NH(2) or 2F) were: 3F(3)(Ac-F(3)18A-NH(2)), 3F(14)(Ac-F(14)18A-NH(2)), 4F(Ac-F(3,14)18A-NH(2)), 5F(Ac-F(11,14,17) 18A-NH(2)), 6F(Ac-F(10,11,14,17)18A-NH(2)), and 7F(Ac-F(3,10,11,14,17) 18A-NH(2)). Measurements of aqueous solubility, HPLC retention time, exclusion pressure for penetration into an egg phosphatidylcholine (EPC) monolayer, and rates of EPC solubilization revealed an abrupt increase in the hydrophobicity between peptides 4F and 5F; this was accompanied by increased ability to associate with phospholipids. The peptides 6F and 7F were less effective, indicating a limit to increased hydrophobicity for promoting lipid interaction in these peptides. Despite this marked increase in lipid affinity, these peptides were less effective than apoA-I in activating the plasma enzyme, lecithin:cholesterol acyltransferase, with 5F activating LCAT the best (80% of apoA-I). Peptides 4F, 5F, and 6F were equally potent in inhibiting LDL-induced monocyte chemotactic activity. These studies suggest that an appropriate balance between peptide-peptide and peptide-lipid interactions is required for optimal biological activity of amphipathic peptides. These studies provide a rationale for the design of small apoA-I-mimetics with increased potency for atherosclerosis inhibition.
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PMID:Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. 1144 Nov 37

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare genetic disorder of the lipid metabolism caused by the absence of LCAT activity in plasma. It is not generally accompanied by atherosclerosis in spite of low high-density lipoprotein cholesterol levels nor by diabetes mellitus. However, reports of long-term follow-up or autopsy findings are rare, and the true incidence of atherosclerosis in LCAT deficiency is not clear. We report on the long-term observation of a patient with familial LCAT deficiency who developed renal failure, diabetes mellitus, and marked atherosclerosis. The patient died of sepsis from foot ulcers 7 years after starting hemodialysis and 13 years after the diagnosis. Marked atherosclerosis characterized by medial calcification in small arteries was observed at autopsy. The genesis of the atherosclerosis seemed to be on the basis of a combination of factors.
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PMID:Marked atherosclerosis in a patient with familiar lecithin: cholesterol acyltransferase deficiency associated with end-stage renal disease and diabetes mellitus. 1168 7

The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr-/-) and apoE (apoE-/-) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr-/- LCAT-/- double knockout mice, compared with LDLr-/- mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 +/- 28 versus 61 +/- 20 mg/g protein) and EC (102 +/- 27 versus 61+/- 27 mg/g). ApoE-/- LCAT-/- mice fed the atherogenic diet, compared with apoE-/- mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 +/- 62 versus 109 +/- 33 mg/g) and EC (101 +/- 23 versus 69 +/- 20 mg/g) than did the apoE-/- mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated + monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr-/- mice and a 3-fold increase in the apoE-/- mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr-/- and apoE-/- mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE-/- background, an increased plasma concentration of apoB lipoproteins.
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PMID:Lecithin:cholesterol acyltransferase deficiency increases atherosclerosis in the low density lipoprotein receptor and apolipoprotein E knockout mice. 1171 20

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare cause of severe hypoalphalipoproteinemia, but the affected subjects are surprisingly not particularly prone to premature coronary heart disease. We studied oxidative stress in lcat-/- mice and their cross-breed with apolipoprotein-E knockout mice (apoE-/-xlcat-/-) by measuring vascular ring superoxide production and plasma phospholipid (PL)-bound F2-isoprostane levels and their relationship with aortic atherosclerosis. Compared with wild type control (lcat+/+), lcat-/- and lcat+/- mice showed a 4.9- (p = 0.003) and a 2.1-fold (p = 0.04) increase in plasma PL-F2-isoprostane levels, respectively. There was also a 3.6- (p < 0.0001) and 2.9-fold (p = 0.003) increase in the area under the curve for the aortic ring superoxide excursion by lucigenin-derived chemiluminescence. A comparison of apoE-/-xlcat+/+ mice with wild type control mice showed a more modest 2.1- (p = 0.04) and 2.2-fold (p < 0.00001) increase in these respective markers. Surprisingly, the apoE-/-xlcat-/- mice showed a paradoxical normalization in both oxidation markers. Furthermore, by fast protein liquid chromatography separation, we observed an associated retention and redistribution of serum paraoxonase activities to the non-high density lipoprotein fractions in both the apoE-/-xlcat-/- and apoE-/-xlcat+/- mice. Aortic atherosclerotic lesions in male apoE-/-xlcat-/- and apoE-/-xlcat+/- mice were reduced by 52 (p = 0.02) and 24% (p = 0.46), respectively. Our data suggest that LCAT-deficient mice are associated with an increased oxidative stress that is paradoxically reversed in a hyperlipidemic background, possibly due to the redistribution of paraoxonase. This modulation of oxidative stress may in part contribute to the reduced atherosclerosis seen in the apoE-/- xlcat-/- mice.
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PMID:Oxidative stress is markedly elevated in lecithin:cholesterol acyltransferase-deficient mice and is paradoxically reversed in the apolipoprotein E knockout background in association with a reduction in atherosclerosis. 1180 74

Lipid and lipoprotein profiles, and enzymes for the lipid metabolism were compared between cord and adult blood. Consistent with previous reports, the major lipoprotein in cord blood was high-density lipoprotein (HDL), and that in adult blood was low-density lipoprotein (LDL). The level of apolipoprotein E (apo E) in cord blood was almost equivalent to that in adult blood, while other apolipoproteins and lipids were all lower than the adult level. In cord blood, apo E-rich HDL cholesterol represented more than 30% of total HDL cholesterol (around 11% in adult), and the concentration was about twice of that in adult blood. This apo E-rich HDL cholesterol was poorly esterified (E/T 56%) compared with that in adults (93%). The lecithin:cholesterol acyltransferase (LCAT) activity in cord blood was extremely low, while the activity and mass of cholesteryl ester transfer protein (CETP) were higher than those in adult blood. The apo E genotype did not show influences on total cholesterol, LDL cholesterol, total HDL cholesterol, and apo E rich HDL cholesterol levels in cord blood, as opposed to those in adult blood. The association of D442G mutation of the CETP gene with the increased HDL cholesterol in adult blood was not seen in cord blood. Rather, the mutation was associated with low total cholesterol and LDL cholesterol levels in cord blood. These results indicate that, in fetus, the character and metabolism of HDL, especially of apo E-rich HDL cholesterol, are distinct from those in adults.
Atherosclerosis 2002 Mar
PMID:Unique character and metabolism of high density lipoprotein (HDL) in fetus. 1188 35


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