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)

Lipoprotein peroxidation, especially the modification of apolipoprotein B-100, has been implicated to play an important role in the pathogenesis of atherosclerosis. However, there have been few detailed insights into the chemical mechanism of derivatization of apolipoproteins during oxidation. In the present study, we provide evidence that the formation of the toxic pollutant acrolein (CH2=CH-CHO) and its conjugate with lysine residues is involved in the oxidative modification of human low density lipoprotein (LDL). Upon incubation with LDL, acrolein preferentially reacted with lysine residues. To determine the structure of acrolein-lysine adduct in protein, the reaction of acrolein with a lysine derivative was carried out. Employing Nalpha-acetyllysine, we detected a single product, which was identified to be a novel acrolein-lysine adduct, Nalpha-acetyl-Nepsilon-(3-formyl-3,4-dehydropiperidino )lysine. The acid hydrolysis of the adduct led to the derivative that was detectable with amino acid analysis. It was revealed that, upon in vitro incubation of LDL with acrolein, the lysine residues that had disappeared were partially recovered by Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine. In addition, we found that the same derivative was detected in the oxidatively modified LDL with Cu2+ and that the adduct formation was correlated with LDL peroxidation assessed by the consumption of alpha-tocopherol and cholesteryl ester and the concomitant formation of cholesteryl ester hydroperoxide. Enzyme-linked immunosorbent assay that measures free acrolein revealed that a considerable amount of acrolein was released from the Cu2+-oxidized LDL. Furthermore, metal-catalyzed oxidation of arachidonate was associated with the formation of acrolein, indicating that polyunsaturated fatty acids including arachidonate represent potential sources of acrolein generated during the peroxidation of LDL. These results indicate that acrolein is not just a pollutant but also a lipid peroxidation product that could be ubiquitously generated in biological systems.
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PMID:Acrolein is a product of lipid peroxidation reaction. Formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins. 963 57

Advanced glyco-oxidation end products (AGEs) generate oxygen free radicals that potentiate the development of atherosclerosis. Thus, AGEs may potentiate the aggregation of human platelets through oxidative stress. AGE-bovine serum albumin (BSA) and AGE-poly-L-lysine were evaluated for aggregation of human platelets. Superoxide in platelet-rich plasma (PRP) was measured using lucigenin-derived chemiluminescence. The platelet aggregation induced by ADP or U46619 was potentiated by preincubation with AGE-BSA, by 40% and by 59%, P < .05, respectively, vs BSA. Aggregation was increased by AGEs in a dose-dependent manner. The production of superoxide was significantly greater in PRP incubated with AGE-BSA vs BSA. The other Maillard reaction products, such as Amadori-, pentosidine-, and carboxymethyl lysine (CML)-BSA had no effect. Superoxide dismutase or indomethacin abolished the enhancing effect of AGEs on the platelet aggregation. AGEs potentiate platelet aggregation possibly with superoxide anions and prostanoids. AGE-induced potentiation of platelet aggregation may be involved in the development of atherosclerosis.
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PMID:Increased aggregation of human platelets produced by advanced glycation end products in vitro. 967 28

Lipoprotein(a) [Lp(a)], an independent risk factor for the development of atherosclerosis, contains an apolipoprotein(a) [apo(a)] moiety covalently linked to a LDL moiety. Apo(a) is a glycoprotein homologous to plasminogen as it contains multiple repeats of a lysine binding domain resembling plasminogen kringle IV (K.IV). The multiple K.IV repeats can be differentiated in ten types that show a variation in their lysine binding capacity. Since K.IV type 10 shows the highest conservation of the amino acids postulated to form the lysine binding pocket, this kringle is suggested to be the main lysine binding site of apo(a). Recently, a T-->C polymorphism in the apo(a)-gene was reported, leading to a Met-->Thr substitution at amino acid position 66 of K.IV type 10, in the vicinity of the postulated lysine binding pocket. To investigate the significance of this substitution on some in vitro characteristics of Lp(a), the affinity for lysine-Sepharose and the binding affinity for limited plasmin digested des AA fibrin (Desafib-X) of the two subtypes was determined using plasma of donors homozygous for the polymorphism. These studies revealed a large heterogeneity in the binding characteristics, irrespective of the subtype. The comparison of the allele frequencies of this polymorphism in 155 patients having symptomatic atherosclerosis versus 153 normolipidemic controls revealed no significant differences. In conclusion, this study suggests that the presence of either a Met66 or a Thr66 residue in K.IV type 10 of apo(a) has no consequences for the binding characteristics of Lp(a) toward lysine-Sepharose or Desafib-X, nor is it associated with the presence of symptomatic atherosclerosis.
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PMID:The functional and clinical significance of the Met-->Thr substitution in Kringle IV type 10 of apolipoprotein(a). 968 31

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. alpha-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with diabetes. We studied the effect of the alpha-dicarbonyl compound methylglyoxal (MG) on the physicochemical and biological properties of LDL. MG dose-dependently modifies LDL, as indicated by the formation of fluorescent products and the increase of a net negative charge. MG (10 mmol/l) induced major modifications of arginine residues (up to 85%) and minor lysine modifications (less than 6%). MG-LDL preparations generated small amounts of superoxide anion radicals as measured by the reduction of cytochrome c, but this was not accompanied by peroxidation of the polyunsaturated fatty acids of MG-LDL. MG-LDL showed diminished recognition and uptake by the human LDL receptor in cultured cells and a markedly increased plasma clearance rate in vivo in rats. The reduced association and degradation of 125I-oxidised LDL by murine macrophages indicates recognition of MG-LDL by a scavenger receptor. Surprisingly, MG-LDL caused significantly less cholesteryl ester synthesis in murine macrophages, as compared to native LDL and oxidised or acetylated LDL. Highly modified MG-LDL did not induce activation of human endothelial cells, as measured by the expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1.
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PMID:Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein. 979 11

Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.
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PMID:Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity. 983 67

The modification of long-lived proteins with advanced glycation endproducts (AGEs) has been hypothesised to contribute to the development of pathologies associated with uremia. Imidazolone and N(epsilon)-(carboxymethyl)lysine (CML) are common epitopes of AGE-modified proteins. Imidazolone is a reaction product of arginine with 3-deoxyglucosone (3-DG) which is markedly accumulated in uremic serum. CML is produced by glycoxidation, and represents a marker of oxidative stress. The specificity of anti-imidazolone antibody that we had developed was further examined using ELISA. The antibody reacted only with imidazolone derived from 3-DG and arginine, but did not react at all with the other imidazolone-like compounds such as reaction products of glyoxal, methylglyoxal, glucosone with arginine or a reaction product of 3-DG with creatine. Further, to determine if AGEs are involved in the development of atherosclerosis in hemodialysis (HD) patients, we studied the localisation of imidazolone and CML in the aortas obtained from HD patients by immunohistochemistry using the anti-imidazolone and anti-CML antibodies. Imidazolone and CML were localised in all atherosclerotic aortic walls of the HD patients. In conclusion, imidazolone and CML are localised in the characteristic lesions of atherosclerosis in HD patients. These results strongly suggest that imidazolone produced by 3-DG, and CML produced by glycoxidation may contribute to the development of atherosclerosis in uremic patients.
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PMID:Immunohistochemical detection of imidazolone and N(epsilon)-(carboxymethyl)lysine in aortas of hemodialysis patients. 984 92

Methylglyoxal is formed in vivo by spontaneous decomposition of triose phosphate intermediates in aerobic glycolysis. It may also be formed during oxidative degradation of both carbohydrates (pentoses and ascorbate) and lipids (arachidonate). In addition to reaction with arginine residues to form imidazolone adducts, methylglyoxal reacts with lysine residues in protein to form N(epsilon)-(carboxyethyl)lysine (CEL) and the imidazolium crosslink, methylglyoxal-lysine dimer (MOLD). Like the glycoxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and glyoxal-lysine dimer (GOLD) which are formed on reaction of glyoxal with protein, CEL and MOLD increase in lens proteins and skin collagen with age. CML and CEL also increase in skin collagen in diabetes, while all four compounds increase in plasma proteins in uremia. Overall, CML, CEL, GOLD and MOLD are quantitatively the major biomarkers of the Maillard reaction in tissue proteins. GOLD and MOLD, in particular, are present at 10-50 fold higher concentrations than the fluorescent crosslink, pentosidine. Together, these dicarbonyl-derived advanced glycation endproducts (AGEs) represent the major chemical modifications that accumulate in tissue proteins with age and in chronic diseases such as diabetes and atherosclerosis.
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PMID:Chemical modification of proteins by methylglyoxal. 984 96

To better understand the role of advanced glycation end products (AGEs) in atherogenesis, we developed specific antibodies against different immunological epitopes of AGE structures, including Nepsilon-(carboxymethyl)lysine-protein adduct (CML) and a structure(s) other than CML (nonCML), and demonstrated the immunohistochemical localization of CML- and nonCML-epitopes in atherosclerotic lesions of human aorta, which were obtained at autopsy from 20 nondiabetic patients (12 males and eight females; mean age, 60.8+/-16.7 years). Monoclonal anti-CML antibody (6D12) recognized not only AGE-modified proteins, but also CML-modified proteins. On the other hand, polyclonal anti-nonCML antibody reacted to AGE-modified proteins, but not to CML-modified proteins. Both antibodies were unreactive to the early-stage products of glycation, including fructose-modified butyloxycarbonyl-lysine and fructose-epsilon-aminocaproic acid. Atherosclerotic lesions included diffuse intimal thickening (DIT), fatty streaks (FS), atherosclerotic plaques (AP) and complicated lesions. An immunohistochemical analysis showed both CML- and nonCML-epitopes to be found along the collagen fibers in DIT in subjects more than 40 years old, but not in subjects less than 40 years old. CML-epitopes accumulated mainly in the cytoplasm of macrophage/foam cells, while nonCML-epitopes accumulated exclusively in the extracellular spaces in FS. APs showed the CML-epitope stored macrophage/foam cells, and the accumulation of both CML- and nonCML-epitopes in the lipid-rich fibrous area. An immunohistochemical analysis with a monoclonal antibody against oxidized low density lipoprotein (FOH1a/DLH3) showed the presence of this antigen within the cytoplasm of the macrophage/foam cells in atherosclerotic lesions, which were also positive for the CML-epitopes. These findings thus suggest that the heterogeneous localization of AGEs in atherosclerotic lesions depends on their different epitopes, and that a close link, therefore, exists between the peroxidation of LDL and the formation of AGEs in atherosclerotic lesions.
Atherosclerosis 1998 Nov
PMID:Immunohistochemical localization of different epitopes of advanced glycation end products in human atherosclerotic lesions. 986 39

Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry. Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes. We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference.
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PMID:Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. 989 15

Although advanced glycation end products (AGEs) are increased in the serum and tissues of patients with end-stage renal disease, little is known about the role of AGEs in atherogenesis. We therefore carried out an immunohistochemical study on the accumulation of AGEs and apolipoprotein B in the human aortas of diabetic and nondiabetic subjects with end-stage renal disease. The atherosclerotic lesions included diffuse intimal thickening, fatty streaks and atherosclerotic plaque. We used antibodies against two different epitopes of AGE structures, i.e. an Nepsilon-(carboxymethyl)lysine-protein adduct (CML) and a structure(s) other than CML (nonCML). The area that was positive for an antigen as a percentage of the total area (%Ar) was determined morphometrically, using an NIH-image program. In diffuse intimal thickening, atherosclerotic plaque and tunica media, the %Ar of CML and nonCML was significantly greater in diabetic or nondiabetic subjects with end-stage renal disease than in control subjects without end-stage renal disease. In fatty streaks, the %Ar of nonCML was significantly greater in nondiabetic subjects with end-stage renal disease than in control subjects, while no difference in the %Ar of CML was found between the subjects with or without end-stage renal disease. Nondiabetic subjects with end-stage renal disease showed a significantly increased %Ar of apolipoprotein B in fatty streaks and atherosclerotic plaque than the control subjects. The %Ar of CML and nonCML significantly correlated with the duration of hemodialysis in diffuse intimal thickening and atherosclerotic plaque of subjects with end-stage renal disease, but not in fatty streaks. On the other hand, the %Ar was not related to the duration of diabetes in any of the lesions in the diabetic subjects with end-stage renal disease. In diffuse intimal thickening and atherosclerotic plaque, subjects with end-stage renal disease showed a significant correlation between the %Ar of apolipoprotein B and AGEs (CML and nonCML), as well as their immunohistochemical colocalization. These results suggest that impaired AGE clearance may cause the increased accumulation of AGEs in the aortic wall of subjects with end-stage renal disease, thus resulting in the rapid progression of atherosclerosis. The accumulation of AGEs may be related to an enhanced LDL deposition in atherosclerotic lesions of subjects with end-stage renal disease.
Atherosclerosis 1999 Jan
PMID:Increased advanced glycation end products in atherosclerotic lesions of patients with end-stage renal disease. 992 May 7


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