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)

Increased blood pressure induces functional and structural changes of the vascular endothelium. Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension. It can be demonstrated by pharmacological or physiological tests. Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation. It may be caused by a reduction in the activity of NO-endothelial synthase (NOSe) related to: 1) a deficit in substrate (L-arginine), 2) an inhibition by asymmetrical dimethylarginine, 3) a deficit in the cofactor tetrahydrobiopterin (BH4). However, the increase in oxidative stress, a producer of superoxide radicals which combine with NO to form peroxynitrates (ONOO-), is the determining factor. It is related to activation of membranous NAD(P)H oxidases initiated by the stimulation of activating mecanosensors of protein C kinase. The message is amplified by oxidation of BH4 which transforms the NOSe into a producer of superoxide radicals. A cascade of auto-amplification loops leading to atherosclerosis and its complications is then triggered. The superoxide radicals and the peroxynitrates oxidise the LDL-cholesterol. They activate the nuclear factor-kappaB which controls the genes stimulating the expression of many proteins: angiotensinogen and AT1 receptors which stimulate the sympathetic system, receptors of oxidised LDL, adhesion and migration factors (ICAM-1, VCAM-1, E-selectin and MCP-1), pro-inflammatory cytokins (interleukines and TNF-alpha), growth factors (MAP kinases), plasminogen activator inhibitor 1. The monocytes and smooth muscle cells produce metalloproteinases and pro-inflammatory cytokins which destabilise the atheromatous plaque and favourise vascular remodelling. Inshort, the endothelial dysfunction due to hypertension plays a role in a complex physiopathological process and is a marker of future cardiovascular events.
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PMID:[Hypertension, endothelial dysfunction and cardiovascular risk]. 1710 Jan 43

Increased risk of thrombosis, with propitious conditions for fibrin deposition, along with upregulation of inflammation, are important factors that enhance plaque formation in atherosclerosis. Evidence supporting the role of anticoagulant protein C (PC) as an inflammatory agent has emerged, supplementing its well-known function as an anticoagulant. Thus, we sought to examine whether a PC deficiency would lead to an enhanced response to an acute arterial hyperplasic challenge. The presentation of early arterial inflammation was studied using a copper/silicone arterial cuff model of accelerated focal neointimal remodeling in mice with a heterozygous total deficiency of PC (PC+/-). Increased inflammation, cell proliferation, cell migration, fibrin elevation, and tissue necrosis were observed in the treated arteries of PC+/- mice, as compared to arteries of equally challenged age- and gender-matched WT mice. These results indicate that PC+/- mice subjected to this challenge displayed enhanced focal arterial inflammation and thrombosis, leading to larger neointimas and subsequent localized occlusion, as compared to their WT counterparts.
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PMID:Focal arterial inflammation is augmented in mice with a deficiency of the protein C gene. 1713 75

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with a high prevalence of cardiovascular disease due to accelerated atherosclerosis, as well as an increased risk of venous thromboembolism. Many of these clinical features have been attributed to the high prevalence of autoantibodies that are directed against phospholipid-bound antigens and that induce prothrombotic effects and disturb endothelial cell function. We conducted a case-control study in a cohort of female patients with SLE and in age-matched and sex-matched normal individuals. Patients had significantly higher levels of plasma inflammatory markers, but their overall coagulation status assessed by prothrombin fragment 1 + 2 and D-dimer plasma levels was not different from controls. Resistance against activated protein C (APC), assessed by a thrombin generation-based as well as an activated partial thromboplastin time-based method, however, was increased in patients. This defect was neither due to factor V Leiden carriership or to the use of oral contraceptives. This acquired form of APC resistance was due to proinflammatory changes associated with lower plasma levels of free protein S. In conclusion, acquired APC resistance may be an important determinant of the risk of thrombosis in patients with SLE, probably due to an active cross-talk between inflammation and coagulation systems.
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PMID:The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus. 1717 22

Haemostatic and inflammatory markers have been hypothesised to mediate the relationship of social class and cardiovascular disease (CVD). We investigated whether a range of inflammatory/haemostatic markers are associated with social class independent of chronic diseases and behavioural risk factors in a population-based sample of 2682 British men aged 60-79 without a physician diagnosis of CVD, diabetes or musculoskeletal disease requiring anti-inflammatory medications. Men in lower social classes had higher mean levels of C-reactive protein, fibrinogen, interleukin-6, white blood cell count, von Willebrand factor (vWF), factor VIII, activated protein C (APC) resistance, plasma viscosity, fibrin D-dimer and platelet count, compared to higher social class groups; but not of tissue plasminogen activator antigen, haematocrit or activated partial prothrombin time. After adjustment for behavioural risk factors (smoking, alcohol, physical activity and body mass), the associations of social class with vWF, factor VIII, APC resistance, plasma viscosity, and platelet count though weakened, remained statistically significant, while those of other markers were considerably attenuated. In this study of older men without CVD, the social gradient in inflammatory and haemostatic markers was substantially explained by behavioural risk factors. The effect of socio-economic gradient on the factor VIII-vWF complex, APC resistance, plasma viscosity and platelet count merits further study.
Atherosclerosis 2008 Apr
PMID:Relationships of inflammatory and haemostatic markers with social class: results from a population-based study of older men. 1739 87

Recently, the C-allele of polymorphism rs2359612 (VKORC1: c.283+837C>T) in the VKORC1 gene has been reported to represent a major risk factor for coronary heart disease (CHD), stroke, and aortic dissection in Chinese patients. VKOR activity itself is the rate-limiting step in gamma-carboxylation of vitamin K-dependent coagulation factors (factors II, VII, IX, X, protein C, S, and Z) and proteins of calcium metabolism (matrix Gla protein and osteocalcin). Gamma-carboxylation is essential for the biological activity of these proteins that have been previously hypothesised to play a role in the pathogenesis of atherosclerosis. It was the objective of this study to analyse the VKORC1 genotype frequency in patients with CHD and controls from Northern Germany and to investigate the association of VKORC1 and CHD risk in patients with an European background. CHD patients (n = 901) and healthy controls (n = 521) were part of the PopGen biobank. Case and control samples were matched for ethnic and geographic origin, age and gender. After typing German CHD patients and control individuals, no evidence for a statistically significant association was detected between VKORC1 genotype and CHD phenotype. Also stratification for gender and myocardial infarction yielded no significant results. In conclusion, the discrepant association findings in Chinese and German populations may be explained by ethnic differences in genetic and perhaps environmental predisposition, modifying the polygenic CHD phenotype by interacting with VKORC1 variants and thus conferring disease susceptibility in some populations, but not in others.
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PMID:Functional promoter polymorphism in the VKORC1 gene is no major genetic determinant for coronary heart disease in Northern Germans. 1754 3

T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR(-/-) controls. PD-L1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD4(+) and CD8(+) T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD4(+) T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD4(+) T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation.
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PMID:Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. 1785 43

Inflammation plays a role in vascular injury and repair. The inflammatory acute phase protein C-reactive protein (CRP) has emerged as a powerful predictor of cardiovascular events. CRP serum levels display rapid rise following infection or tissue damage. CRP is a pentraxin regulated mainly by IL-6. Several studies established correlation between CRP levels and cardiovascular disease risk and the long term clinical outcome after acute coronary syndrome. Such correlation has yet to be proven regarding CRP and atherosclerosis. A growing body of evidence supports a role for CRP in the cardiovascular pathogenesis. CRP binds to LDL, VLDL and oxidized LDL, promoting complement activation. CRP induces tissue factor secretion from monocytes, enhances the expression of adhesion molecules and inhibits production of nitric oxide and prostacycline by human endothelial cells. The in-vitro studies which utilize recombinant CRP are criticized by studies in which preservatives and contaminants rather than CRP are responsible for the biological effects. Nevertheless, transgenic mice expressing human CRP have been shown to have an increased thrombotic risk. This data supports an active role of CRP in the evolvement of vascular damage rather than being just a marker, but its role in the development of atherosclerosis is not yet clear. There is no evidence to lowering vascular risk by reducing CRP levels but weight loss, exercise, statins and smoking secession all decrease CRP blood levels.
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PMID:[C-reactive protein and atherothrombosis--a prognostic factor or a risk factor?]. 1825 51

Occlusions of retinal veins (central and branch) represent multifactorialy-conditioned disease involving presumably older patients, in whom the changes of retinal vessels caused by hypertension and atherosclerosis present the most important pathophysiological factors for development of this disease. In last years, the intensive scientific research is focused to the explanation of the role of the defects of the coagulations cascade. Especially in younger patients, the most often mentioned defect of the coagulations cascade is called as APC-resistance. Up to 95% of all patients with APC-resistance are carriers of so called Leiden mutation. The aim of our study was to establish the prevalence of the ACP-resistance in 92 patients with central or branch occlusion of the retinal vein verified by means of angiography treated at the Department of Ophthalmology, Faculty Hospital, Olomouc, Czech Republic, EU, during the period 1999-2005. The control group consisted of 40 patients without any vascular, eye-related disease. In the group of patients with occlusion of the retinal vein, the prevalence of the APC-resistance was 10.9% and in the control group 5%. In the group of patients 55 years old and younger the prevalence of the ACP-resistance was 14.3%, in patients older than 55 years it was 5.6%. According to the relatively small groups of patients, the established difference did not reach the level of statistical evidence. Results of our study confirmed the conclusions of previously published papers that the prevalence of the APC-resistance is not significantly higher in patients with retinal vein occlusion according to the prevalence in controls.
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PMID:[Disturbances of the plasma coagulation defects in retinal venous occlusions]. 1863 Jan 61

Antiphospholipid syndrome is considered to be associated with a hypercoagulable state that leads to stroke and other ischemic events, and is currently diagnosed based on the modified Sapporo criteria that was proposed in 2006. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, the level of beta2-glycoprotein I-dependent anticardiolipin antibody, lupus anticoagulant (LA), and IgG anticardiolipin antibody are commonly measured. Recently, phosphatidylserine dependent anti-prothrombin antibody has been suggested to be closely related to LA. aPL is an independent risk factor for a first-ever ischemic stroke, especially in young female patients. It is still debatable whether aPL is a marker for recurrent stroke risk. The precipitating factors for the occurrence of stroke are beta2-GPI-dependent aCL, aGPL, and aCL levels of greater than 40, and the simultaneous presence of LA. Several mechanisms are considered to be involved in the thrombotic process in patients with antiphospholipid antibodies. Activation of protein C is impaired in patients with aPL. Beta2-GPI has simultaneous procoagulant and anticoagulant effects. Cardiac valvular involvement, which could be the cause of cardiogenic embolism, is prevalent in patients with aCL. In addition, the presence of aPL is associated with the development of atherosclerosis. Recently, it has been proposed that endothelial cells, monocytes, and platelets were reported to be activated by beta2-GPI: further, p38 mitogen-activated protein kinase has been reported to be phosphorylated. Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL. For cases of cryptogenic ischemic stroke and positive aPL antibodies, antiplatelet therapy is reasonable. Oral anticoagulation with a target international normalized ratio (INR) of 2 to 3 is reasonable for patients with ischemic stroke who meet the criteria for antiphospholipid syndrome with venous and arterial occlusive disease in multiple organs.
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PMID:[Ischemic stroke with antiphospholipid antibody]. 1897 2

Valproic acid is one of the most frequently prescribed antiepileptic drugs for the therapy of generalized and focal epilepsies. Valproate induces a variety of hemostatic disorders such as thrombocytopenia, abnormal platelet function, hypofibrinogenemia, and decreased concentrations of von Willebrand factor, and it rarely causes serious bleeding complications. It may also lead to atherosclerosis and thrombosis. However, there is still lack of knowledge about the incidence and occurrence of these particular side effects. In this prospective systematic study, we assessed the early effects of sodium valproate on both pro- and anticoagulatory factors, homocysteine, and lipoprotein (a) in 24 newly diagnosed epileptic children treated with valproate. Valproate causes decreased factor VII levels, platelet count, factor VIII, Protein C, fibrinogen, and increased lipoprotein (a) levels. To the best of our knowledge, our report is the first in the medical literature, which describes that valproate significantly reduces factor VII levels even during short-term therapy.
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PMID:Valproate-associated coagulopathies in children during short-term treatment. 1948 38


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