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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that lipoprotein(a) [Lp(a)], an atherogenic lipoprotein that contains apolipoprotein(a), which shares partial structural homology to plasminogen, binds to a plasmin-modified fibrin surface, and we have postulated that this interaction may be atherogenic. Moderate elevations in blood homocysteine, a relatively common condition, predispose to premature atherosclerosis. The reasons for this are not established. We now report that homocysteine, at concentrations as low as 8 microM, significantly increases the affinity of Lp(a) for fibrin. Homocysteine induces a 20-fold increase in the affinity between Lp(a) and plasmin-treated fibrin and a 4-fold increase with unmodified fibrin. Lp(a) binding is inhibited by epsilon-aminocaproic acid, indicating lysine binding site specificity. Homocysteine does not enhance the binding of Lp(a) to other surface-bound proteins. Cysteine, glutathione, and N-acetylcysteine also increase the affinity between Lp(a) and fibrin. Homocysteine does not affect the binding of low density lipoprotein or plasminogen to fibrin, nor does it alter the gel-filtration elution pattern of Lp(a). Immunoblot analysis documents the fact that homocysteine partially reduces Lp(a). These results suggest that homocysteine alters the intact Lp(a) particle so as to increase the reactivity of the plasminogen-like apolipoprotein(a) portion of the molecule. The observation that sulfhydryl amino acids increase Lp(a) binding to fibrin suggests a biochemical relationship between sulfhydryl compound metabolism, thrombosis, and atherogenesis.
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PMID:Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. 143 9

The complete amino acid sequence of the liver-synthesized apolipoprotein B (apoB) species, apoB 100, has been derived from cloned cDNA. The protein consists of 4536 amino acids (+ a 27 amino acid signal sequence). Cysteine is clustered in the N-terminal 1/10 of the protein, suggesting the presence of a stabilized tertiary structure in this part of the molecule. Three types of structure are suggested to be of importance for the binding of the protein to lipids; (i) hydrophobic sequences with a high probability for beta-sheet structure, (ii) strict amphipathic beta-sheets, and (iii) amphipathic alfa-helices. An apoB 100 molecule is completed within 10-14 min and secreted after approximately 30 min, 1/3 of which is due to the transfer through the endoplasmic reticulum (ER), while 2/3 is spent in the Golgi apparatus. ApoB 100 is co-translationally N-glycosylated and 25% of the oligosaccharide chains is processed in the Golgi compartment. Other posttranslational modifications that have been discussed include covalent acylation and phosphorylation. It has also been suggested that the lipid moiety of the apoB 100 lipoproteins are modified during the passage through the Golgi apparatus. The site of lipoprotein assembly is suggested to be separated from the site of apoB 100 synthesis, and apoB 100 appears to be co-translationally bound to the ER membrane and from this transferred to the ER lumen. Based on these observations a model for the assembly of apoB 100 lipoproteins is discussed in this paper. The intestinal derived apoB species, apoB 48, has a molecular mass of 210 kDa and appears to correspond to the N-terminal 48% of apoB 100. The mechanism by which apoB 48 is formed is still not known. Available data indicate that the protein is formed within the intestinal cells, these data also argue against the possibility that apoB 48 is formed by posttranslational proteolysis of apoB 100. The formation of a separate apoB 48 mRNA by alternative splicing has been suggested, based on the observation of a 7 kb mRNA which corresponds to the 5' portion of the apoB 100 mRNA. However, the most abundant apoB mRNA species found in the intestine have a size that corresponds to that of the apoB 100 mRNA, furthermore the observation that apoB 48 appears to terminate in a 7.5 kb exon that appears to lack alternative splice sites, does not favour the possibility of alternative splicing.
Atherosclerosis 1987 Nov
PMID:Apolipoprotein B: structure, biosynthesis and role in the lipoprotein assembly process. 331 51

Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury.
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PMID:Agonist-induced peroxynitrite production from endothelial cells. 817 19

Oxidized low density lipoprotein (LDL) may play a significant role in atherosclerosis. We have investigated the effect of pH on the oxidation of LDL by iron or copper. When LDL was oxidized by iron in the presence of cysteine in either Hanks' balanced salt solution (HBSS) or Ham's F-10 medium, an acidic pH greatly decreased the lag period and increased the rate of formation of hydroperoxides and thiobarbituric acid-reactive substances (TBARS), and increased its uptake by macrophages. There was a dose-dependent increase of LDL oxidation at acidic pH in the presence of increasing concentrations of cysteine. When LDL was oxidized by copper in HBSS, an acidic pH increased the lag phase before the rapid formation of conjugated dienes, hydroperoxides, and TBARS, but increased its uptake by macrophages. Similar results were obtained using Ham's F-10 medium. Cysteine (100 microM) inhibited the modification of LDL by copper in HBSS at both pH 7.4 and 5.5 As atherosclerotic lesions may be acidic, these observations may help to explain why LDL oxidation occurs locally at these sites.
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PMID:Oxidation of low density lipoprotein by iron or copper at acidic pH. 884 77

Cysteine proteases have traditionally been viewed as lysosomal mediators of terminal protein degradation. However, recent findings refute this limited view and suggest a more expanded role for cysteine proteases in human biology. Several newly discovered members of this enzyme class are regulated proteases with limited tissue expression, which implies specific roles in cellular physiology. These roles appear to include apoptosis, MHC class II immune responses, prohormone processing, and extracellular matrix remodeling important to bone development. The ability of macrophages and other cells to mobilize elastolytic cysteine proteases to their surfaces under specialized conditions may also lead to accelerated collagen and elastin degradation at sites of inflammation in diseases such as atherosclerosis and emphysema. The development of inhibitors of specific cysteine proteases promises to provide new drugs for modifying immunity, osteoporosis, and chronic inflammation.
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PMID:Emerging roles for cysteine proteases in human biology. 907 57

Several studies have reported that moderate hyperhomocysteinemia is related to an increased risk for atherosclerosis, but few data are available with regard to any other thiol compound having a potential vascular toxicity. Therefore, we measured both total cysteine and homocysteine plasma levels in patients with hyperlipidemia (242 males and 147 females, 41-65 years old). Homocysteine was higher in males than in females, 13.2+/-4.1 versus 11.1+/-3.4 micromol/l (P<0.0001). The mean cysteine level was 243.3+/-45.7 micromol/l in the whole study population. The subjects were split in two groups, symptomatic patients with cardiovascular disease (n = 106) and asymptomatic subjects (n = 283). Blood pressure, smoking status, total cholesterol, LDL-cholesterol and triglycerides did not statistically differ between groups, but the mean HDL-cholesterol level was lower in symptomatic patients (1.24+/-0.38 versus 1.42+/-0.41, P<0.0001). Cysteine levels were higher in patients with cardiovascular disease than in asymptomatic patients, respectively 254.7+/-47.7 versus 239.1+/-44.3 micromol/l (P = 0.003). A similar result was found for homocysteine, respectively 13.1+/-4.3 versus 12.2+/-3.9 micromol/l (P = 0.05). To analyse whether cysteine levels were related to atherosclerosis independently of age, adjusted levels were compared between asymptomatic patients with normal carotid arteries (n = 176), carotid atherosclerosis (n = 107) and symptomatic patients (n = 106). Age adjusted cysteine levels differed significantly between groups (P = 0.027) while the P-value was of borderline significance for homocysteine (P = 0.09). Odds ratios for having symptomatic cardiovascular disease were 1.81 (95% CI, 1.02-3.21) and 2.05 (95% CI, 1.16-3.60) for the mid and highest tertiles of cysteine using the lowest as the reference. After adjustment in a multivariate model including age, sex, and creatinine, the odds ratio for disease remained significant between the highest tertile versus the lowest (OR = 1.89). Adjusted odds ratios were found to be weaker when homocysteine tertiles were compared. Our data suggest that plasma total cysteine is a risk factor for atherosclerosis in hyperlipidemic patients.
Atherosclerosis 1999 Sep
PMID:Cysteine is a cardiovascular risk factor in hyperlipidemic patients. 1048 86

Cysteine-rich 61 (Cyr61, CCN1) and connective tissue growth factor (CTGF, CCN2) are growth factor-inducible immediate-early gene products found in blood vessel walls and healing cutaneous wounds. We previously reported that the adhesion of endothelial cells, platelets, and fibroblasts to these extracellular matrix-associated proteins is mediated through integrin receptors. In this study, we demonstrated that both Cyr61 and CTGF are expressed in advanced atherosclerotic lesions of apolipoprotein E-deficient mice. Because monocyte adhesion and transmigration are important for atherosclerosis, wound healing, and inflammation, we examined the interaction of THP-1 monocytic cells and isolated peripheral blood monocytes with Cyr61 and CTGF. THP-1 cells and monocytes adhered to Cyr61- or CTGF-coated wells in an activation-dependent manner and this process was mediated primarily through integrin alpha(M)beta(2). Additionally, expression of alpha(M)beta(2) on human embryonic kidney 293 cells resulted in enhanced cell adhesion to Cyr61. Consistent with these data, a GST-fusion protein containing the I domain of the integrin alpha(M) subunit bound specifically to immobilized Cyr61 or CTGF. We have also investigated the requirement of cell surface heparan sulfate proteoglycans (HSPGs) as coreceptors for monocyte adhesion to Cyr61. Pretreatment of monocytes with heparin or heparinase I resulted in partial inhibition of cell adhesion to Cyr61. However, monocytes, but not fibroblasts, were capable of adhering to a Cyr61 mutant deficient in heparin binding activity. Collectively, these results show that activated monocytes adhere to Cyr61 and CTGF through integrin alpha(M)beta(2) and cell surface HSPGs. However, unlike fibroblast adhesion to Cyr61, cell surface HSPGs are not absolutely required for this adhesion process.
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PMID:Identification of integrin alpha(M)beta(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions. 1203 76

Oxidised low density lipoprotein (LDL) may play a role in atherogenesis. We have investigated some of the mechanisms by which the thiol cysteine and the disulphide cystine can influence the oxidation of LDL by copper ions. Cysteine or cystine (100 microM) inhibited the oxidation of native LDL by copper in a simple phosphate buffer. One of the mechanisms by which cysteine (or more likely its oxidation products in the presence of copper) and cystine inhibited LDL oxidation was by decreasing the binding of copper to LDL (97% inhibition). Cysteine, but not cystine, rapidly reduced Cu(2+) to Cu(+). This may help to explain the antioxidant effect of cysteine as it may limit the amount of Cu(2+) that is available to convert alpha-tocopherol in LDL into the prooxidant alpha-tocopherol radical. Cysteine (but not cystine) had a prooxidant effect, however, toward partially oxidised LDL in the presence of a low copper concentration, which may have been due to the rapid breakdown of lipid hydroperoxides in partially oxidised LDL by Cu(+) generated by cysteine. To prove that cysteine can cause the rapid breakdown of lipid hydroperoxides in LDL, we enriched LDL with lipid hydroperoxides using an azo initiator in the absence of copper. Cysteine, but not cystine, increased the rate of lipid hydroperoxide decomposition to thiobarbituric acid-reactive substances (TBARS) in the presence of copper.
Atherosclerosis 2003 Jul
PMID:Mechanisms by which cysteine can inhibit or promote the oxidation of low density lipoprotein by copper. 1286 Feb 54

Lipid-modified proteins are classified based on the identity of the attached lipid, a post- or co-translational modification required for their biological function. At least five different lipid modifications of cysteines, glycines and other residues on the COOH- and NH(2)-terminal domains have been described. Cysteine residues may be modified by the addition of a 16-carbon saturated fatty acyl group by a labile thioester bond (palmitoylation) or by prenylation processes that catalyze the formation of thioether bond with mevalonate derived isoprenoids, farnesol and geranylgeraniol. The NH(2)-terminal glycine residues may undergo a quite distinct process involving the formation of an amide bond with a 14-carbon saturated acyl group (myristoylation), while glycine residues in the COOH-terminal may be covalently attached with a cholesterol moiety by an ester bond. Finally, cell surface proteins can be anchored to the membrane through the addition of glycosylphosphatidylinositol moiety. Several lines of evidence suggest that lipid-modified proteins are directly involved in different steps of the development of lesions of atherosclerosis, from leukocyte recruitment to plaque rupture, and their expression or lipid modification are likely altered during atherogenesis. This review will briefly summarize the different enzymatic pathways of lipid modification and propose a series of lipid-modified proteins that can be used as biomarkers for cardiovascular disease.
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PMID:Lipid-modified proteins as biomarkers for cardiovascular disease: a review. 1619 83

Tangier disease (TD) is a hereditary disorder characterized by the severe deficiency or absence of high-density lipoprotein cholesterol (HDL-C). TD is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, most of which are located in the extracellular loops and nucleotide-binding domains. Here we describe the first case of TD carrying a missense mutation in a transmembrane alpha-helix of ABCA1. A 31-year-old Japanese woman had an extremely low level of HDL-C (1mg/dl) and yellowish tonsillar swelling, leading to the diagnosis of TD. The proband was homozygous for a point mutation of T4978C in exon 37, which results in the substitution of cysteine-1660 to arginine (C1660R) in the 8th transmembrane segment of ABCA1. Her parents, grandmother, and brother were found to be heterozygous for the same mutation. Both peripheral blood leukocytes from the patient and HEK293 cells transfected with T4978C-mutated ABCA1 normally expressed ABCA1 on the plasma membrane and had normal apolipoprotein A-I-binding ability. However, apolipoprotein A-I-mediated efflux of cholesterol and phospholipids was markedly diminished in HEK293 cells transfected with T4978C-mutated ABCA1. These results suggest that this mutant is normally translated and exists as a stable product with normal localization, yet is functionally defective. Cysteine-1660 appears to be a critical residue for cholesterol transport of ABCA1.
Atherosclerosis 2009 Sep
PMID:A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease. 1934 98


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