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)

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.
Atherosclerosis 2004 May
PMID:Genetic risk for restenosis after coronary balloon angioplasty. 1513 68

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins, have been demonstrated to reduce cardiovascular morbidity and mortality in patients with a wide range of cholesterol levels. Numerous cholesterol-independent effects of statins that may limit atherosclerosis are probably related to inhibition of the geranylgeranylation of GTP-binding intracellular signaling proteins and involve: improved vasoreactivity, mostly through increased NO bioavailability; decreased expression of proinflammatory cytokines (interleukin-6, interleukin-1 beta, tumor necrosis factor alpha), C-reactive protein, chemokines, matrix metalloproteinases, and tissue factor with the subsequent inhibition of thrombin generation; reduced platelet activity; increased thrombomodulin expression; enhanced fibrinolysis, regulation of angiogenesis and immunomodulation. However, the clinical relevance of multiple protective effects induced by statins has not been clarified yet.
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PMID:New nonlipid effects of statins and their clinical relevance in cardiovascular disease. 1517 91

Recently, leptin has been suggested as a possible cause of atherosclerotic disease. In the present study, we have investigated in postmenopausal women (n = 60; age: 52 +/- 13) the relationship between circulating levels of leptin, oxidized LDL (Ox-LDL) and other biochemical and anthropometric variables of atherosclerotic risk. In addition, we have evaluated soluble thrombomodulin (sTM) as a marker of endothelial damage. An additional study was conducted in a subgroup of obese subjects to determine the short-term effects of weight loss on selected variables. Ox-LDL showed a positive correlation with leptin circulating levels (r = 0.65, P < 0.0001). A significant association was also found between Ox-LDL and body mass index (r = 0.69, P < 0.0001), waist-to-hip ratio (r = 0.50, P < 0.0001), insulin levels (r = 0.65, P < 0.0001), HOMA index (r = 0.55, p < 0.0001) and sTM (r = 0.74, P < 0.0001) levels. After multivariate regression analysis leptin was still related to Ox-LDL levels (P = 0.007). In obese women who completed the program of weight reduction, leptin changes persisted as a significant predictor of plasma changes in Ox-LDL levels. These findings suggested a novel link between leptin and Ox-LDL, possibly involved in atherosclerotic disease.
Atherosclerosis 2004 Jul
PMID:Circulating leptin is associated with oxidized LDL in postmenopausal women. 1518 58

Adiponectin has antiatherogenic properties and attenuates endothelial inflammatory responses. CD146 is a novel cell adhesion molecule localized at the endothelial junction. In renal failure, endothelial dysfunction and atherosclerosis are almost universal. We studied possible correlations between adiponectin, CD146, and other markers of endothelial cell injury in patients with chronic renal failure (CRF) on conservative treatment and patients with and without diabetic nephropathy maintained on chronic ambulatory peritoneal dialysis (CAPD). We assessed adiponectin, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1), thrombin-activatable fibrinolysis inhibitor, and endothelial function/injury markers: von Willebrand factor, thrombomodulin, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule, and CD146. Adiponectin was elevated in patients with CRF and on CAPD. It correlated significantly, with PAI-1, thrombin-activatable fibrinolysis inhibitor, intercellular adhesion molecule, VCAM, and CD146 in nondiabetics on CAPD. In diabetics, CAPD adiponectin correlated positively with C146 and VCAM and negatively with PAI and TFPI. In multivariate regression analysis, only CD146 remained a positive predictor of adiponectin in all CAPD patients. In CRF, adiponectin correlated with CD146. In healthy volunteers, adiponectin correlated with TFPI and CD146. Elevated adiponectin related to CD146 may be the expression of a counterregulatory response aimed at mitigating the consequences in endothelial damage and increased cardiovascular risk in renal failure.
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PMID:Adiponectin is related to CD146, a novel marker of endothelial cell activation/injury in chronic renal failure and peritoneally dialyzed patients. 1535 72

TLR4 and CD14 are two components of the LPS receptor complex, which are considered to play a key role in the pathogenesis of atherosclerosis. TLR4/Asp299Gly and CD14/C-260T polymorphisms are thought to modulate the activity of this complex. The aim of the study was to examine the association between the TLR4/Asp299Gly and CD14/C-260T polymorphisms, plasma levels of the soluble receptor CD14 (sCD14), and the incidence of coronary heart disease (CHD) in a prospective cohort (the PRIME Study) of 9758 healthy men aged 50-59 years recruited in France and Northern Ireland. A nested case-control design was used, comparing the 249 participants who developed a CHD event during the 5-year follow-up with 492 population- and age-matched control subjects. The two polymorphisms were genotyped and baseline plasma concentrations of sCD14 were measured. None of the two polymorphisms, or sCD14 levels, either considered alone or in combination, were associated with the risk of CHD. The CD14/C-260T allele was associated with increased plasma concentrations of soluble thrombomodulin and vascular cell adhesion molecule-1 and, to a lesser extent, sCD14. No relationship was observed between the TLR4 polymorphism and, any of the inflammatory and endothelial markers measured. The TLR4/Asp299Gly and CD14/C-260T polymorphisms and plasma sCD14 concentrations do not appear as significant predictors of the risk of CHD in healthy individuals.
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PMID:TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study. 1536 17

In a previous case control study of myocardial infarction (MI), we identified risk associated with the combination of two variants in the thrombomodulin (TM) gene (-1208-1209TTdelTT and A455V) and an interaction with increased body mass index (BMI). The rare alleles at these two common variant sites in the TM gene occur in most individuals on the same allele (V/delTT) and are in strong linkage disequilibrium (Delta=0.67, P <0.0005). We have extended these findings in a prospective study of 2700 UK middle age men; the second Northwick Park Heart Study (NPHSII), in which 227 coronary heart disease (CHD) events have been reported to date. Risk was analysed by tertile of BMI, systolic blood pressure (SBP) and triglyceride. The strongest risk for the V/delTT haplotype was in the mid- and top-tertile of triglyceride; RR 1.95 (CI 1.12-3.40) and 1.77 (CI 1.02-3.09), respectively, compared to non-carriers in the lowest tertile (after adjusting for age, practice, smoking, SBP, BMI; interaction P=0.016). No significant risk was identified for increased triglyceride levels in those with the common TM haplotype. There was a suggestion for greater inflammatory response (C-reactive protein levels, CRP) in those with V/delTT compared to those with the common allele, as triglyceride levels increased. Overall, these findings may suggest that the common TM allele confers protection against the adverse CHD effect of either plasma triglyceride-containing lipoproteins, or the underlying atherosclerotic mechanism of the metabolic syndrome, and that this process is defective in carriers of V/delTT.
Atherosclerosis 2004 Nov
PMID:A combination of two common thrombomodulin gene variants (-1208-1209TTdelTT and A455V) influence risk of coronary heart disease: a prospective study in men. 1548 71

Coronary artery disease is a leading cause of mortality in highly developed societies. This occurs in spite of growing therapeutic opportunities. Atherosclerosis begins as a functional or/and structural damage of endothelium, which in turn causes its discontinuation and impairs humoral and secreting function. Haemostasis plays an important role in the progression of atherosclerosis and development of cardiac complications--acute coronary syndromes. Research still continues to determine precisely role of each of haemostasis disorders in increased risk of coronary artery disease and its complications. The aim of this paper is to review the literature data concerning haemostatic risk factors and their role of development of coronary artery disease. Fibrinogen, thrombocytes, factor VII, factor VIII, von Willebrand factor (vWF), thrombomodulin (TM), plasminogen activator inhibitor--type 1 (PAI-1), tissue-plasminogen activator (t-PA) and other haemostatic factors, were described as more or less helpful in estimation of risk of occurrence of coronary artery disease and its cardiovascular complications. Only some of the described hematologic factors were verified so far in large prospective studies, and were recognized as independent risk factors of cardiovascular diseases.
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PMID:[Role of the hemostatic system in pathogenesis of atherosclerosis as the main etiology of coronary ischemia] [corrected]. 1551 28

The principles of Virchov's triad appear to be operational in atherothrombosis or arterial thrombosis: local flow changes and particularly vacular wall damage are the main pathophysiological elements. Furthermore, alterations in arterial blood composition are also involved although the specific role and importance of blood coagulation is an ongoing matter of debate. In this review we provide support for the hypothesis that activated blood coagulation is an essential determinant of the risk of atherothrombotic complications. We distinguish two phases in atherosclerosis: In the first phase, atherosclerosis develops under influence of "classical" risk factors, i.e. both genetic and acquired forces. While fibrinogen/fibrin molecules participate in early plaque lesions, increased activity of systemic coagulation is of no major influence on the risk of arterial thrombosis, except in rare cases where a number of specific procoagulant forces collide. Despite the presence of tissue factor - factor VII complex it is unlikely that all fibrin in the atherosclerotic plaque is the direct result from local clotting activity. The dominant effect of coagulation in this phase is anticoagulant, i.e. thrombin enhances protein C activation through its binding to endothelial thrombomodulin.The second phase is characterized by advancing atherosclerosis, with greater impact of inflammation as indicated by an elevated level of plasma C-reactive protein, the result of increased production influenced by interleukin-6. Inflammation overwhelms protective anticoagulant forces, which in itself may have become less efficient due to down regulation of thrombomodulin and endothelial cell protein C receptor (EPCR) expression. In this phase, the inflammatory drive leads to recurrent induction of tissue factor and assembly of catalytic complexes on aggregated cells and on microparticles, maintaining a certain level of thrombin production and fibrin formation. In advanced atherosclerosis systemic and vascular wall driven coagulation becomes more important and elevated levels of D-dimer fragments should be interpreted as markers of this hypercoagulability.
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PMID:Blood coagulation and the risk of atherothrombosis: a complex relationship. 1557 98

Endothelial membrane-bound thrombomodulin is a high affinity receptor for thrombin to inhibit coagulation. We previously demonstrated that the thrombin-thrombomodulin complex restrains cell proliferation mediated through protease-activated receptor (PAR)-1. We have now tested the hypothesis that thrombomodulin transduces a signal to activate the endothelial nitric-oxide synthase (NOS3) and to modulate G protein-coupled receptor signaling. Cultured human umbilical vein endothelial cells were stimulated with thrombin or a mutant of thrombin that binds to thrombomodulin and has no catalytic activity on PAR-1. Thrombin and its mutant dose dependently activated NO release at cell surface. Pretreatment with anti-thrombomodulin antibody suppressed NO response to the mutant and to low thrombin concentration and reduced by half response to high concentration. Thrombin receptor-activating peptide that only activates PAR-1 and high thrombin concentration induced marked biphasic Ca2+ signals with rapid phosphorylation of PLC(beta3) and NOS3 at both serine 1177 and threonine 495. The mutant thrombin evoked a Ca2+ spark and progressive phosphorylation of Src family kinases at tyrosine 416 and NOS3 only at threonine 495. It activated rapid phosphatidylinositol-3 kinase-dependent NO synthesis and phosphorylation of epidermal growth factor receptor and calmodulin kinase II. Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3. Prestimulation of thrombomodulin did not affect NO release but reduced Ca2+ responses to thrombin and histamine, suggesting cross-talks between thrombomodulin and G protein-coupled receptors. This is the first demonstration of an outside-in signal mediated by the cell surface thrombomodulin receptor to activate NOS3 through tyrosine kinase-dependent pathway. This signaling may contribute to thrombomodulin function in thrombosis, inflammation, and atherosclerosis.
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PMID:Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II. 1612 27

Cardiovascular diseases (CVD), being mostly a clinical manifestation of atherosclerosis, are the main cause of mortality in patients with chronic renal failure (CRF). It is now generally accepted that the first step in atherosclerosis is endothelial dysfunction. Recently, oxidative stress (SOX) has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction both in general and uremic populations. The aim of the present study was to establish the effect of two different method of dialysis therapy: hemodialysis (HD) and continuous peritoneal dialysis (CAPD) on the markers of SOX: lipid peroxides, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies against oxidized LDL (OxLDL-Ab), and endothelial injury: antigen of the von Willebrand factor (vWF : Ag), soluble thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) in 43 patients with CRF. Compared with the control subjects, patients with CRF showed a significant increase in plasma concentrations of Cu/Zn SOD, which was more elevated in HD than in CAPD group. The lipid peroxide levels were increased only in the post-HD samples, whereas OxLDL-Ab were more elevated in HD than in CAPD group. Markers of endothelial injury were significantly higher in dialyzed patients relative to controls, and were positively correlated themselves as well as with Cu/Zn SOD levels. The patients on HD and CAPD are exposed to increased SOX as well as to endothelial injury. The association between Cu/Zn SOD and the endothelial injury markers suggests the possible effect of oxidative stress on endothelial dysfunction in CRF patients.
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PMID:[Method of dialysis therapy and selected markers of oxidative stress and endothelial injury in patients with chronic renal failure]. 1613 May 97


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