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)

A series of pro-oxidant and antioxidant enzymes, such as the NADPH oxidase system, maintain the redox state in the vessel wall. A major component of NADPH oxidase is p22(phox), which is implicated in atherosclerosis. We prospectively studied the association of the histidine (H)(72)-->tyrosine (Y) mutation in p22(phox) with the severity and progression/regression of coronary artery disease (CAD), plasma lipid levels, clinical events, and response to treatment with fluvastatin in a well-characterized population. Genotypes were determined by polymerase chain reaction and restriction digestion with RsaI enzyme in 368 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Subjects with CC genotype (n=157) were identified by the presence of 396-bp and 113-bp products on gel electrophoresis. Those with TT (n=39) were identified by the presence of 316-bp, 113-bp, and 80-bp products, and those with CT (n=172) by the presence of 396-bp, 316-bp, 113-bp, and 80-bp products. Baseline and final plasma levels of lipids and the baseline severity of CAD were not significantly different among the genotypes. In the placebo group, subjects with the mutation had a 3- to 5-fold greater loss in mean minimum lumen diameter (MLD) (TT: -0.15+/-0.15; CT: -0.17+/-0.26; and CC: -0.03+/-0.22 mm; P=0. 006) and lesion-specific MLD (TT: -0.15+/-0.06; CT: -0.18+/-0.03; and CC: -0.06+/-0.03 mm; P=0.038) than those without. Progression was also more (TT: 8/17 [47%]; CT: 35/73 [48%]; and CC: 17/62 [27%]) and regression less (TT: 0/17 [0%]; CT: 1/73 [1%]; and CC: 11/72 [18%]) common in those with the mutation (P=0.002). The C(242)T mutation in p22(phox), involved in maintaining the redox state in the vessel wall, is associated with progression of coronary atherosclerosis in the LCAS population.
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PMID:A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis. 1070 Apr 37

A preponderance of dense low density lipoprotein (LDL) particles is associated with an increased risk of coronary heart disease. It has been shown that dense LDL levels can be modified by diet. We investigated the contribution of polymorphisms in the genes for apolipoprotein (apo) B, apo AIV, lipoprotein lipase (LPL) and cholesterol ester transfer protein (CETP) to variation in the changes in plasma concentrations of dense LDL between a high saturated and a high polyunsaturated fatty acid diet. A total of 46 freeliving individuals (19 men and 27 women) completed a crossover trial with two dietary interventions of 4 weeks each, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat). Overall, the change in dense LDL between the saturated and polyunsaturated fat period was 0.17+/-0.33 mmol/L and this change was similar in men and women. Of the polymorphisms studied only variation in the apo AIV gene causing the substitution of histidine for glutamine at position 360 (Q360H) was associated with significant differences in the change in dense LDL concentration. Apo AIV Q/H individuals (n=6) showed a three-fold greater change in dense LDL cholesterol unadjusted for Lp(a) levels than Q/Q individuals (0.46+/-0.27 versus 0.12+/-0.31 mmol/L, p=0.02). The greater decrease in dense LDL cholesterol with an increase in polyunsaturated fat seen in those with the apo AIV H360 variant, who represent roughly 10% of the general population, suggests that they may benefit most from a PUFA rich lipid lowering diet.
Atherosclerosis 2000 Apr
PMID:Genetic factors associated with response of LDL subfractions to change in the nature of dietary fat. 1072 89

Pseudohypertension is the artifactual elevation of blood pressure that occurs secondary to noncompressible blood vessels. It has been described in patients with uremia, diabetes mellitus, and severe atherosclerosis. If unrecognized, the condition may lead to inappropriate and potentially harmful therapy. We report a case of pseudohypertension in a 65-year-old man with diffuse scleroderma. His blood pressure as assessed by conventional sphygmomanometry was at least 240/135 to 145 mm Hg. Intra-arterial blood pressure was found to be 107/52 mm Hg. The severe rise in blood pressure as measured by sphygmomanometry led to the concern of scleroderma renal crisis and potentially harmful therapy. Intra-arterial pressure monitoring confirmed the presence of pseudohypertension, however. This is the first reported case of pseudohypertension in a patient with diffuse scleroderma.
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PMID:Pseudohypertension in a patient with diffuse scleroderma. 1127 2

Defective binding of apolipoprotein E (apoE) to heparan sulfate proteoglycans (HSPGs) is associated with increased risk of atherosclerosis due to inefficient clearance of lipoprotein remnants by the liver. The interaction of apoE with HSPGs has also been implicated in the pathogenesis of Alzheimer's disease and may play a role in neuronal repair. To identify which residues in the heparin-binding site of apoE and which structural elements of heparan sulfate interact, we used a variety of approaches, including glycosaminoglycan specificity assays, (13)C nuclear magnetic resonance, and heparin affinity chromatography. The formation of the high affinity complex required Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147 from apoE and N- and 6-O-sulfo groups of the glucosamine units from the heparin fragment. As shown by molecular modeling, using a high affinity binding octasaccharide fragment of heparin, these findings are consistent with a binding mode in which five saccharide residues of fully sulfated heparan sulfate lie in a shallow groove of the alpha-helix that contains the HSPG-binding site (helix 4 of the four-helix bundle of the 22-kDa fragment). This groove is lined with residues Arg-136, Ser-139, His-140, Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147. In the model, all of these residues make direct contact with either the 2-O-sulfo groups of the iduronic acid monosaccharides or the N- and 6-O-sulfo groups of the glucosamine sulfate monosaccharides. This model indicates that apoE has an HSPG-binding site highly complementary to heparan sulfate rich in N- and O-sulfo groups such as that found in the liver and the brain.
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PMID:New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. 1150 May

1. Ghrelin is the recently identified endogenous ligand for the cloned growth hormone secretagogue receptor (GHS-R). We have characterized for the first time the binding of human [125I-His(9)]-ghrelin to normal human and rat tissue and demonstrated expression of this 'orphan' receptor that has previously been predicted to exist from mRNA. Furthermore, we have discovered that [125I-His(9)]-ghrelin density is significantly increased in atherosclerosis. 2. [125I-His(9)]-Ghrelin bound to non-diseased human heart (left ventricle) with an association rate constant (k(obs)) of 0.16+/-0.004 min(-1), a dissociation rate constant of 0.068+/-0.0005 min(-1) (kinetically derived K(D) of 0.1 nM; n=5 individuals+/-s.e.mean), a K(D) of 0.43+/-0.08 nM and B(max) of 7.8+/-0.9 fmol mg(-1) protein (n=6 individual+/-s.e.mean). 3. Specific [125I-His(9)]-ghrelin binding was to the human vasculature including aorta, coronary, pulmonary, arcuate arteries in the kidney and saphenous veins. In rat tissues, binding sites were also localized to the vasculature in peripheral tissues as well as the granular layer of the cerebellum in the CNS. 4. [125I-His(9)]-Ghrelin binding was significantly up-regulated (3 - 4 fold) in both atherosclerotic coronary arteries and saphenous vein grafts with advanced intimal thickening, compared with normal vessels (P<0.05). 5. Our results suggest that the native receptor for [125I-His(9)]-ghrelin may be widely distributed in the human cardiovascular system. Furthermore, changes in the density of this proposed ghrelin receptor implicates this new transmitter system in the development of atherosclerosis and may therefore represent a novel therapeutic target in the treatment of cardiovascular disease.
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PMID:[125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. 1152 6

We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery. RT-PCR and immunohistochemical staining revealed that the HDC gene was expressed in monocytes/macrophages and T cells in the arterial intima but not in smooth muscle cells in either the arterial intima or the media. A luciferase promoter assay with U937 and Jurkat cells demonstrated that interleukin-4 (IL-4) inhibited the expression of the HDC gene. In contrast, among a scavenger receptor family, IL-4 as well as histamine up-regulated U937 cells to express the LOX-1 gene but not the SR-A gene, which genes encode receptors that scavenge oxidized lipids. These findings suggest that histamine synthesized in the arterial wall participates in the initiation and progression of atherosclerosis and that IL-4 can act as an important inhibitory and/or stimulatory factor in the function of monocytes/macrophages modulated by histamine in relation to the process of atherosclerosis.
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PMID:Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis. 1156 79

Hypochlorous acid (HOCl) is a potent oxidant, which is produced in vivo by activated phagocytes. This compound is an important antibacterial agent, but excessive or misplaced production has been implicated in a number of human diseases, including atherosclerosis, arthritis, and some cancers. Proteins are major targets for this oxidant, and such reaction results in side-chain modification, backbone fragmentation, and cross-linking. Despite a wealth of qualitative data for such reactions, little absolute kinetic data is available to rationalize the in vitro and in vivo data. In this study, absolute second-order rate constants for the reactions of HOCl with protein side chains, model compounds, and backbone amide (peptide) bonds have been determined at physiological pH values. The reactivity of HOCl with potential reactive sites in proteins is summarized by the series: Met (3.8 x 10(7) M(-1) x s(-1)) > Cys (3.0 x 10(7) M(-1) x s(-1)) >> cystine (1.6 x 10(5) M(-1) x s(-1)) approximately His (1.0 x 10(5) M(-1) x s(-1)) approximately alpha-amino (1.0 x 10(5) M(-1) x s(-1)) > Trp (1.1 x 10(4) M(-1) x s(-1)) > Lys (5.0 x 10(3) M(-1) x s(-1)) >> Tyr (44 M(-1) x s(-1)) approximately Arg (26 M(-1) x s(-1)) > backbone amides (10-10(-3) M(-1) x s(-1)) > Gln(0.03 M(-1) x s(-1)) approximately Asn (0.03 M(-1) x s(-1)). The rate constants for reaction of HOCl with backbone amides (peptide bonds) vary by 4 orders of magnitude with uncharged peptide bonds reacting more readily with HOCl than those in a charged environment. These kinetic parameters have been used in computer modeling of the reactions of HOCl with human serum albumin, apolipoprotein-A1 and free amino acids in plasma at different molar excesses. These models are useful tools for predicting, and reconciling, experimental data obtained in HOCl-induced oxidations and allow estimations to be made as to the flux of HOCl to which proteins are exposed in vivo.
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PMID:Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds. 1159 38

Caveolin is an integral membrane protein that interacts with cholesterol in glycosphingolipid-rich rafts at the cell surface. We have examined the interaction of recombinant His-tagged caveolin-1 with cholesterol and 7-keto cholesterol, the most abundant non-enzymatically formed oxysterol found in oxidised LDL and atheromatous plaque. Our data show that caveolin-1 is able to interact with both sterols. This might have consequences for sterol transport and the signalling properties of cells during atherosclerosis.
Atherosclerosis 2001 Nov
PMID:Interaction of caveolin with 7-ketocholesterol. 1168 6

Urokinase plasminogen activator (uPA) has been implicated in the healing responses of injured arteries, but the importance of its various properties that influence smooth muscle cell (SMC) proliferation and migration in vivo is unclear. We used three recombinant (r-) forms of uPA, which differ markedly in their proteolytic activities and abilities to bind to the uPA receptor (uPAR), to determine, which property most influences the healing responses of balloon catheter injured rat carotid arteries. After injury, uPA and uPAR expression increased markedly throughout the period when medial SMCs were rapidly proliferating and migrating to form the neointima. Perivascular application of uPA neutralizing antibodies immediately after injury attenuated the healing response, significantly reducing neointima size and neointimal SMC numbers. Perivascular application of r-uPAwt (wild type uPA) or r-uPA/GDF (r-uPA with multiple mutations in its growth factor-like domain) doubled the size of the neointima. Four days after injury these two uPAs nearly doubled neointimal and medial SMC numbers in the vessels, and induced greater reductions in lumen size than injury alone. Proteolytically inactive r-uPA/H/Q (containing glutamine rather than histidine-204 in its catalytic site) did not affect neointima or lumen size. Also, in contrast to the actions of proteolytically active uPAs, tissue plasminogen activator (tPA) did not affect the rate of neointima development. We conclude that uPA is an important factor regulating the healing responses of balloon catheter injured arteries, and its proteolytic property, which cannot be mimicked by tPA, greatly influences SMC proliferation and early neointima formation.
Atherosclerosis 2001 Dec
PMID:Urokinase plasminogen activator augments cell proliferation and neointima formation in injured arteries via proteolytic mechanisms. 1173 Aug 9

A 68-year-old man was admitted to St Marianna University Hospital on account of loss of consciousness with left hemiplegia. During the hospital recovery course with a rehabilitation procedure, the patient's blood pressure was very unstable, fluctuating between high (210/110 mmHg) and low (110/70 mmHg) values accompanied by a fainting sensation. A second stroke of left hemiplegia took place 1 month later. Afterwards, his condition worsened to tetraplegia with dysarthria. Three months later, lung cancer with multiple metastasis including his left neck was found and he died from adynamic ileus 6 months after the onset of the present illness. Autopsy revealed nearly complete atheromatous obstruction and more than 50% stenosis, respectively, of his right common and internal/external carotid arteries. His intracranial arterial trunks and main branches were all patent with localized atherosclerosis of only moderate degree. The pathology of the brain existed predominantly in the right hemisphere in the border zone area between the anterior and middle cerebral arteries systematically with numerous disseminated foci of complete or incomplete necrosis, white matter and gray matter being involved independently. Involvement of centrum semiovale white matter is more extensive and intensive than that of gray matter. Of the gray matter, cerebral cortex as well as striatum, periventricular (the third ventricle) gray and cerebellar cortex was involved. The specific characteristic topography and distribution of the lesions together with their histopathology are described in detail with illustration. It is concluded that this case represents an outstanding example of hemodynamic cerebral circulatory insufficiency doubly caused by hemilateral carotid artery stenosis and repeated episodes of systemic hypotension.
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PMID:An autopsy case of hemilaterally dominant and systematic/extensive border zone infarction: sequela of preceding atherosclerotic obstruction of one common carotid artery followed by repeated episodes of systemic hypotension. 1183 34


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