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)

During progression of atherosclerosis the overlying endothelial cells alter their expression of some surface molecules. Circulating levels of such molecules may be quantified. We investigated the effect of omega-3 fatty acids (n-3 FA) on the levels of tissue plasminogen activator antigen, von Willebrand factor, and the soluble forms of thrombomodulin, P-selectin, E-selectin, and vascular cell adhesion molecule-1 in 54 patients with coronary heart disease. Twenty-three of the patients had taken 5.1 g/d n-3 FA for 6 months (group I) and 31 were given corn oil as placebo (group II). For another 4 weeks ("the study period") they all got 5.1 g/d of n-3 FA. Compliance was confirmed by demonstration of changes in relevant fatty acids in serum phospholipids. At baseline, significant differences between the groups were found with lower median values of von Willebrand factor (128% versus 147%) and soluble thrombomodulin (24.9 versus 32.5 ng/mL) and higher median values of soluble E-selectin (41.4 versus 35.5 ng/mL) and soluble vascular cell adhesion molecule-1 (573 versus 473 ng/mL) in group I. During the study period differences in changes between the groups were found; tissue plasminogen activator antigen and soluble thrombomodulin decreased (P for difference between the groups 0.001 and 0.015, respectively), whereas soluble E-selectin and soluble vascular cell adhesion molecule-1 increased (P for difference between the groups <0.01 for both) in group II relative to group I. Our results indicate that n-3 FA supplementation decreases hemostatic markers of atherosclerosis, whereas markers of inflammation may be increased. The latter may be the result of lipid peroxidation as a simultaneous decrease of vitamin E and increase in thiobarbituric acid-reactive substances were observed.
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PMID:The effect of supplementation with omega-3 fatty acids on soluble markers of endothelial function in patients with coronary heart disease. 1039 85

Atherogenesis in the vasculature is accelerated by changes in the dynamic equilibrium between endogenous tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1). Increased expression of PAI-1, decreased expression of tissue plasminogen activator, or both can lead to decreased fibrinolytic activity and predispose to thrombosis. Increased concentrations of insulin (and proinsulin) in the plasma increase plasma PAI-1, although the mechanisms of this effect are not known. In addition, it has been observed that basal fibrinolytic activity is decreased in patients with type 2 diabetes; this may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi. Abnormalities in the vessel wall appear to contribute to the increased risk. There is also evidence that PAI-1 content is increased in atherosclerotic lesions of patients with type 2 diabetes, suggesting that interventions to reduce insulin resistance and improve glycemic control may improve the fibrinolytic response. Clinical studies in patients with polycystic ovary syndrome (characterized by insulin resistance, hyperinsulinemia, ovarian androgen overproduction, and impaired fibrinolytic capacity) demonstrated that treatment with troglitazone, an insulin-sensitizing agent, can markedly reduce blood levels of PAI-1. There is also clinical evidence that these agents may contribute to regression of intimal medial thickness in patients with type 2 diabetes, providing further indication that antidiabetic interventions may help inhibit the progression of early atherosclerotic lesions.
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PMID:Insulin resistance and thrombosis: a cardiologist's view. 1041 58

Poor long-term patency and a lack of suitable systemic pharmacologic therapy for the prevention of vein graft failure have prompted the search for effective local gene therapy. Vein grafts are particularly well suited for gene transfer in the clinic because direct access to vein is available during surgical preparation for grafting. In this review, the available animal models are discussed and a new mouse model is highlighted. Recent advances in gene transfer technology are reviewed, including the use of adeno-associated virus and modified adenoviruses that can prolong in vivo transgene expression for months. Gene therapy is intended to reduce early thrombosis, reduce neointima formation, and prevent atherosclerosis in vein grafts. Promising antithrombotic targets include tissue plasminogen activator and thrombomodulin. Nitric oxide synthase, prostacyclin synthase, and tissue inhibitors of metalloproteinases have been used to reduce neointima formation, and vein graft atheroma remains a challenge for the future.
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PMID:Targets for gene therapy of vein grafts. 1057 65

Lipoprotein(a) levels are largely genetically determined and are linked to increased risk of coronary artery disease. The hypothesis that elevated lipoprotein(a) levels lead to decreased fibrinolysis, due to the close structural homology with plasminogen, could in part explain the genesis of this risk, although contrasting results have been obtained in different studies. The aim of our study was to evaluate whether the rate of plasmin formation, enhanced in vitro by a fixed amount of human tissue plasminogen activator after clotting, was related to plasma lipoprotein(a) levels in 45 healthy subjects. Aliquots of human plasma were clotted with calcium chloride and thrombin followed by addition of tissue plasminogen activator. We then measured the time course of plasmin formation, determined as hydrolysis of H-D-valyl-L-leucyl-L-lysine-p-nitroanilide dihydrocortide (S-2251). The log of lipoprotein(a) level was negatively related to the rate of plasmin formation (r(s)=-0.46, P=0. 002), and multiple regression analysis indicated that this relationship was not influenced by the amount of plasminogen, fibrinogen, plasminogen activator inhibitor-1, tissue plasminogen activator, or by the size of apo(a) isoforms. These data support the concept that lipoprotein(a) can inhibit plasminogen activation and plasmin formation and can thereby play an important role in the genesis of atherosclerosis as an antifibrinolytic agent.
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PMID:The rate of plasmin formation after in vitro clotting is inversely related to lipoprotein(a) plasma levels. 1059 11

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been associated with increased risk for myocardial infarction, cardiomyopathy, carotid thickening, and cardiac hypertrophy. However, a conclusive agreement about the role of ACE genotype in the genetics of cardiovascular disease has not yet been reached. This study was undertaken to investigate the relationship of the I/D polymorphism of the ACE gene with carotid intima-media thickness (IMT) and left ventricular mass (LVM) in 175 Chinese patients with mild-to-moderate hypertension. The I/D genotypes were detected by the polymerase chain reaction using primers flanking the polymorphic region in intron 16 of the ACE gene. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. Patients with the DD genotype (n = 41) showed significant greater carotid IMT (1.593 +/- 0.879 v 1.309 +/- 0.703 and 1.171 +/- 0.583 mm, P = .01) but insignificant higher LVM index (123.8 +/- 36.6 v 123.7 +/- 37.4 and 118.2 +/- 33.0 g/m2, P = .61) than did those with the DI (n = 69) and II (n = 65) genotypes. The deletion polymorphism of the ACE gene (P = .04) was a significant predictor for carotid IMT on multiple regression analysis, controlling all the potential confounding factors including age (P = .001), systolic blood pressure (P = .09), smoking (P = .08), and plasma tissue plasminogen activator antigen (P = .03), but the LVM correlated only with age (P = .02), sex (P < .001), and body mass index (P < .001). These results indicated that the DD genotype of the ACE gene could be considered a risk factor for the development of early atherosclerosis in carotid arteries but not for left ventricular hypertrophy in the hypertensive population.
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PMID:Carotid thickening, cardiac hypertrophy, and angiotensin converting enzyme gene polymorphism in patients with hypertension. 1067 81

Localized regulation of fibrinolytic protein gene expression is associated with the histologic extent of atherosclerosis. This regulation may be dependent on the presence of certain fibrinolytic protein gene polymorphisms. The relationship between the plasminogen activator inhibitor (PAI)-1 Hin dIII and the tissue plasminogen activator (t-PA) EcoR1 gene polymorphisms and the extent of coronary artery disease (CAD) were investigated in 49 Caucasian patients with symptomatic CAD. There was a strong association between PAI-1, but not t-PA, gene polymorphisms and the extent of CAD detected by coronary angiography. Patients homozygous for the presence or absence of the PAI-1 HindIII (1/1, 2/2 PAI-1) gene polymorphisms had a significantly greater extent of CAD (number of diseased vessels) than patients with the respective heterozygous forms (vs. 1/2 PAI-1, P&< = 0.05). Stepwise ordinal multiple regression analysis of classic CAD risk factors and fibrinolytic protein genotypes indicated that only the PAI-1 genotypes were predictive of the extent of angiographic CAD (P = 0.019). Analysis of variance between classic risk factors and fibrinolytic protein genotypes identified an association between t-PA genotypes and a history of prior infarction or stroke. Fibrinolytic gene polymorphisms for PAI-1 are associated with the extent of CAD in symptomatic patients and with certain risk factors for coronary atherosclerosis.
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PMID:Gene Polymorphisms for PAI-1 Are Associated with the Angiographic Extent of Coronary Artery Disease. 1076 9

Endothelial cell functions, primarily involving regulated mediator secretion or altered surface protein expression, are vital for normal homeostasis. Endothelial cells secrete the potent vasodilator and anti-platelet agent prostacyclin and nitric oxide, and also the potent vasoconstrictor peptide endothelin-1; they control the selective adhesion and emigration of leukocytes from the bloodstream; and they are the source of circulating von Willebrand factor, tissue plasminogen activator and type 1 plasminogen activator inhibitor. The properties of healthy endothelium ensure that an antithrombotic and anticoagulant balance is maintained in the bloodstream, and provide a tonic vasodilator action that controls blood flow and pressure on a minute-to-minute basis. Disturbances of normal endothelial function are strongly implicated in the pathogenesis of atherosclerosis and autoimmune vasculitic diseases including lupus.
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PMID:Normal endothelial cell function. 1080 85

Low plasma fibrinolytic activity in association with increased plasma plasminogen activator inhibitor 1 (PAI-1) levels has been linked to an increased risk of atherosclerosis in obesity and type 2 diabetes. We tested the hypothesis that troglitazone, which improves insulin sensitivity and lowers plasma insulin levels in insulin-resistant obese subjects and patients with type 2 diabetes, would also lower circulating PAI-1 antigen concentrations and activity. We assessed insulin sensitivity (5-h, 80 mU x m(-2) x min(-1) hyperinsulinemic-euglycemic clamp) and measured plasma PAI-1 antigen and activities and tissue plasminogen activator (tPA) in 14 patients with type 2 diabetes and 20 normal control subjects (10 lean, 10 obese) before and after 3 months of treatment with troglitazone (600 mg/day). At baseline, plasma PAI-1 antigen levels after an overnight fast were significantly higher in the obese (33.5 +/- 4.7 microg/l) and type 2 diabetic subjects (54.9 +/- 6.3 microg/l) than in the lean control subjects (16.3 +/- 3.2 microg/l; P < 0.01 and P < 0.001, respectively). Troglitazone decreased plasma PAI-1 antigen concentrations in the diabetic patients (36.8 +/- 5.0 microg/l; P < 0.001 vs. baseline), but the reduction in the obese subjects did not reach statistical significance (baseline, 33.5 +/- 4.7; after troglitazone, 25.6 +/- 5.2 microg/l). Changes in plasma PAI-1 activity paralleled those of PAI-1 antigen. The extent of the reduction in plasma PAI-1 antigen concentrations in the diabetic patients after troglitazone correlated with the reductions in fasting plasma insulin (r = 0.60, P < 0.05), nonesterified fatty acid (r = 0.63, P < 0.02), and glucose concentrations (r = 0.64, P < 0.02) but not with the improvement in glucose disposal rates during the glucose clamps. Three nonresponders to troglitazone with respect to effects on insulin sensitivity and fasting glucose and insulin levels also had no reduction in circulating PAI-1. In conclusion, troglitazone enhances fibrinolytic system activity in insulin-resistant type 2 diabetic patients. This effect appears to be intimately linked to its potential to lower plasma insulin levels and improve glycemic control through its peripheral tissue insulin-sensitizing effects.
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PMID:Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. 1087 Dec 2

To explore the relationship between disorders of endogenous fibrinolysis and thrombosis in patients with lower extremity ischemia, we measured the activity of tissue plasminogen activator (tPAac) and plasminogen activator inhibitor (PAlac) and the antigens of tissue plasminogen activator (tPAa) and inhibitor (PAla) in plasma from 420 patients treated for lower extremity ischemia. Values and ratios observed were compared with those in healthy volunteers. Additionally, values and ratios in the patients were examined with respect to the severity of ischemia and site of atherosclerotic occlusion or stenosis (pelvic compared with femoropopliteal or crural). Patients with lower extremity ischemia had higher plasma concentrations of PAla (p<0.01) and PAlac (p<0.0001) than healthy volunteers. In patients with rest pain or gangrene, the ratio of tPAac to PAlac was higher than in patients with claudication (p<0.05). The elevation of tPAac in patients with the more severe form of lower extremity ischemia is probably the feedback protective reaction on prothrombotic mechanisms of the organism suffered from severe atherosclerosis. Results did not vary according to the site of occlusion or stenosis. Our study found defects in endogenous fibrinolysis in patients with lower extremity ischemia. A defect in fibrinolysis may contribute to the development of thrombosis in native arteries and bypasses.
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PMID:Endogenous fibrinolysis in patients with lower extremity ischemia. 1094 87

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS), the major androgens secreted by human adrenal glands, were suggested to play a protective role in the pathogenesis of atherosclerosis and coronary heart disease. On the basis of a critical review of all existing studies we concluded that 1) there is no evidence of a protective role of DHEA and DHEAS in women, and 2) men with low plasma DHEA and DHEAS levels can be considered as beings at risk of developing a fatal cardiovascular event. These androgens can interfere with atherogenic process by several mechanisms. They influence enzymes such as glucoso-6-phosphate dehydrogenase, which can modify the lipid spectrum. Furthermore, they can inhibit human platelet aggregation, enhance fibrinolysis, slow down cell proliferation and reduce plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen. We suggest that all these DHEA(S) actions are dependent on sex hormone metabolic pathways. There are still insufficient data to advise DHEA supplementation in elderly men, but this type of hormone replacement therapy merits further studies.
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PMID:Do DHEA/DHEAS play a protective role in coronary heart disease? 1098 71


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