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)

To clarify age-related and lipid-related hemostatic abnormalities in the elderly, we measured the plasma levels of active PAI-1 antigen (aPAI-1), tPA-PAI-1 complex (TPC), plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI), plasmin-alpha 2-PI complex (PIC), and D-dimer, together with the plasma levels of fibrinogen, factor VII (F VII), and thrombin-antithrombin III complex (TAT) and the serum lipid levels in 68 hyperlipidemic and 82 normolipidemic elderly subjects. The aPAI-1 ratio was calculated as aPAI-1/(aPAI-1 + TPC). In the normolipidemic elderly subjects, plasma PIC and D-dimer levels were much higher when compared with healthy young controls, and there was also a decrease in plasma plasminogen and alpha 2-PI levels, an increase in plasma TPC levels, and high plasma F VII and fibrinogen levels. In elderly subjects with type IIb hyperlipidemia, both the plasma aPAI-1 level and the aPAI-1 ratio were significantly increased, while the plasma PIC and D-dimer levels were reduced despite higher plasma F VII, fibrinogen and TAT levels. Both serum total cholesterol and triglyceride levels were correlated positively with plasma F VII and TAT levels and with the TAT/PIC ratio, while only serum triglyceride levels showed a positive correlation with plasma TPC and aPAI-1 levels and with the aPAI-1 ratio. Thus, an increase of fibrinolytic activity appears to occur as part of normal aging to balance the increase of procoagulant activity. However, an imbalance between thrombin activity (increased procoagulant activity) and plasmin activity (hypofibrinolysis) appears to occur in elderly individuals with hyperlipidemia, perhaps resulting in a predisposition to thromboembolic disease.
Atherosclerosis 1993 Nov
PMID:Lipid-related hemostatic abnormalities in the elderly: imbalance between coagulation and fibrinolysis. 829 90

In western societies cardiovascular disease accounts for approximately one of every three deaths, and is a major contributor to chronic debiliation. During the last years our knowledge of factors that contribute to the development and progression of this disease has increased markedly. Elevated serum total cholesterol, hypertension and cigarette smoking are "traditional", well-known risk factors. In addition, low serum levels of high density lipoprotein (HDL) cholesterol predispose to development of disease, whereas in epidemiological studies the role of increased triglycerides is more controversial. During the last years derangements in several haemostatic components in persons who develop cardiovascular disease have been observed. Such alterations include increased plasma concentrations of fibrinogen, Factor VII coagulant activity and plasminogen activator inhibitor-1 (PAI-1). Furthermore, interactions between lipoproteins and haemostatic factors are gradually being disclosed. Serum triglycerides have been shown to correlate both to PAI-1 and to Factor VII. The lipoprotein (a), first described by Berg in 1963, also appears to be a link between lipoprotein metabolism and fibrinolytic function. In addition, linkages are observed between high triglycerides, low HDL cholesterol, reduced glucose tolerance, hyperinsulinemia, obesity, low physical activity, reduced fibrinolytic capacity and increased Factor VII. This clustering of risk factors has been suggested to be a coronary risk syndrome and has been called Reavens syndrome, syndrome X and insulin-resistance syndrome. A more descriptive name, athero-thrombogenic syndrome (ATS), has recently been suggested, thereby indicating that both atherosclerosis and thrombosis contribute to its development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiovascular risk factors: interactive effects of lipids, coagulation and fibrinolysis. 832 48

Six healthy male volunteers were served 4 strictly controlled isoenergetic diets differing in fat (20% or 50% of energy) and fiber contents (2 or 4 g/MJ) for periods of 2 days. The diets were served in random order with at least 5 days separating each diet period. Blood samples for determination of factor VII clotting activity using human (FVIIc) and bovine thromboplastin (FVIIbt), and for assessment of factor VII antigen (FVIIag), tissue-plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI activity, t-PA and euglobulin fibrinolytic activity, and triglyceride and insulin levels were collected regularly on the second day of each diet period. The high-fat diets resulted in significantly increased postprandial FVIIbt levels (peak values: 131% vs. 95%, P < 0.01), and higher postprandial FVIIbt/FVIIag ratios (peak values: 1.42 vs. 1.16, P < 0.01) compared with the low-fat diets. Fibrinolytic variables were not affected by the dietary changes and consistently showed characteristic U-shaped (t-PA and PAI-1 antigen, PAI activity), or inverted U-shaped (t-PA and euglobulin fibrinolytic activity) circadian patterns with troughs and peaks, respectively, at 17:30-21:30 h. The dietary fiber content had no significant influence on any of the measured variables. Our findings indicate that high-fat diets may increase blood thrombogenicity by virtue of augmented postprandial activation of factor VII.
Atherosclerosis 1993 Jul
PMID:Dietary effects on circadian fluctuation in human blood coagulation factor VII and fibrinolysis. 839 16

It is not clear whether elevated levels of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAl-1) in Type 2 diabetes mellitus are the result of obesity or coexistent atherosclerosis. Therefore the relationship between PAl-1 and insulin resistance, determined by the homeostasis model assessment (HOMA) was investigated in a group of 26 insulin-resistant, normotensive newly diagnosed Type 2 diabetic patients with a low probability of atherosclerosis. Compared with a normal control group, closely matched for body mass index (BMI), fibrinolytic activity was depressed in the diabetic patients due to elevated levels of the inhibitor PAl-1, 17.6 (11.1-28) vs 8.4 (4.9-14.1) IU ml-1, p < 0.001. PAl-1 was related to BMI, r = 0.59, p < 0.001 plasma insulin, r = 0.66, p < 0.001; insulin resistance, r = 0.54, p < 0.005 and urinary albumin excretion, r = 0.48, p < 0.01, but not HbA1c or fasting glucose. PAl-1 was not related to blood pressure or plasma triglyceride levels. This study suggests that at the time of diagnosis of Type 2 diabetes mellitus, elevated PAl-1 levels are already linked to other risk factors for vascular disease including hyperinsulinaemia, insulin resistance, and urinary albumin excretion, and this is not the result of obesity or coexistent atherosclerosis.
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PMID:The relationship between plasminogen activator inhibitor-1 and insulin resistance in newly diagnosed type 2 diabetes mellitus. 840 25

A glutamine/histidine polymorphism at residue 360 in apolipoprotein (apo) A-IV that generates two electrophoretically detectable isoforms, apo A-IV-1 and apo A-IV-2, affects the plasma concentration of lipoprotein(a) (Lp[a]) in a healthy population. To verify this unexpected association we analyzed the effect of the apo A-IV polymorphism on Lp(a) serum concentrations in 275 male coronary heart disease patients. Allele frequencies of apo A-IV-1 and apo A-IV-2 were 0.917 and 0.083, respectively. In addition, apo A-IV-1/2 heterozygotes showed a 30% lower geometric mean concentration of Lp(a) than apo A-IV-1/1 homozygotes in this study. The relative frequency of Lp(a) concentrations > 20 mg/dl was significantly increased by a factor of 2.25 in apo A-IV-1/1 homozygotes. Other lipid parameters were not significantly affected by this apo A-IV polymorphism. Because of the relations between Lp(a) and the fibrinolytic system, we also analyzed the effect of the apo A-IV polymorphism on hemostatic variables. Apo A-IV-1/2 heterozygosity was associated with a 70% higher geometric mean plasma concentration of D-dimer, i.e., proteolytic fragments of cross-linked fibrin. Plasma concentrations of prothrombin fragments F1 + F2, fibrinogen, plasminogen, and plasminogen activator inhibitor-1 were unaffected. In conclusion, our results indicate a hitherto unappreciated role of the apo A-IV gene or a closely linked locus for the regulation of Lp(a) metabolism and hemostasis and also possibly for atherosclerosis and thrombosis.
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PMID:Glutamine/histidine polymorphism in apo A-IV affects plasma concentrations of lipoprotein(a) and fibrin split products in coronary heart disease patients. 842 59

Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.
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PMID:Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. 842 60

Tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor antigen (PAI-1), soluble P-selectin and von Willebrand factor antigen (vWf) were measured by ELISA in 41 patients with peripheral vascular disease (PVD), 41 with ischaemic heart disease (HD) and in 46 age and sex matched asymptomatic controls. Increased vWf was found in patients with IHD (p = 0.0002) and in patients with PVD (p = 0.0011) relative to the controls but levels did not differ between the two patients groups. Raised tPA found in both PVD (p = 0.0006) and IHD (p = 0.0061) compared to the controls also failed to differentiate the two groups of patients. Soluble P-selectin was also raised in both groups (p = 0.003 in IHD and p = 0.0102 in PVD) with no difference between the groups. There were no differences in levels of PAI-1 between the groups. In the subjects taken as a whole, there were significant Spearman's correlations between tPA and vWf (r = 0.37, p < 0.001), tPA and triglycerides (r = 0.38, p < 0.001), tPA and P-selectin (r = 0.19, p = 0.032), vWf and age (r = 0.25, p = 0.005) and inversely between vWf and HDL (r = -0.25, p = 0.006). These data support the concept that increased levels of tPA may be important in atherosclerosis, and indicate that soluble P-selectin may be useful in further analysis of the role of platelets and the endothelial cell in this disease.
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PMID:von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. 858 97

We evaluated the genotypes of the angiotensin-converting enzyme (ACE) gene in 101 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) was shown to be more common in subjects with a history of stroke than in those without (relative risk, 1.76; confidence intervals, 1.02 to 3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk, 1.99; confidence intervals, 1.10 to 3.59). DD genotype and a positive family history were strong independent discriminators of cerebral ischemia. Plasma levels of tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history and significantly interacted with TPA levels > 10 ng/mL in such identification. We conclude that in subjects attending a metabolic ward, homozygosity for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with TPA improves such identification.
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PMID:Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke. 862 Mar 47

Diabetes mellitus is associated with disturbances in hemostasis that could contribute to the development of diabetic vascular disease. We investigated the changes in parameters of blood coagulation and the fibrinolytic system and in plasma levels of lipoprotein(a)(Lp(a)) in 124 patients with type II diabetes mellitus and 44 healthy control subjects matched for age and body mass index (BMI) to determine whether hemostatic disturbances may lead to increased cardiovascular mortality. Median levels of fibrinogen (P < 0.0001), thrombin-antithrombin III complex (TAT) (P < 0.005), and plasminogen activator inhibitor-1 (PAI-1) activity (P < 0.05) in plasma were significantly elevated in diabetic patients compared with controls. The median concentration of Lp(a) was significantly higher in diabetic patients than in normal controls (18.2 vs. 12.6 mg/dl. P < 0.0005). Lp(a) levels tended to be elevated in patients with a prolonged history of diabetes. There was no evidence that Lp(a) levels were affected by metabolic control or by type of treatment. Twenty-two diabetics with coronary heart disease (CHD) had significantly higher levels of fibrinogen (P < 0.05), TAT (P < 0.05), and Lp(a) (24.7 vs. 13.7 mg/dl, P < 0.01) than the 51 patients without diabetic angiopathy. Our data indicate that impaired hemostatic balance in diabetes may cause hypercoagulability and may thus contribute to the increased cardiovascular mortality in diabetes.
Atherosclerosis 1996 Feb
PMID:Hypercoagulability and high lipoprotein(a) levels in patients with type II diabetes mellitus. 864 73

Atherosclerosis and postangioplasty restenosis may result from abnormal wound healing. The present studies report that normal human smooth muscle cells are growth inhibited by TGF-beta1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-beta1, yet cells grown from human vascular lesions are growth stimulated by TGF-beta1 and markedly increase collagen synthesis. Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-beta1, and produce similar levels of TGF-beta activity. Membrane cross-linking of 125I-TGF-beta1 indicates that normal human smooth muscle cells express type I, II, and III receptors. The type II receptor is strikingly decreased in lesion cells, with little change in the type I or III receptors. RT-PCR confirmed that the type II TGF-beta1 receptor mRNA is reduced in lesion cells. Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-beta1, implying that signaling remains responsive. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components. This TGF-beta1 receptor dysfunction may be relevant for atherosclerosis, restenosis and related fibroproliferative diseases.
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PMID:Decreased type II/type I TGF-beta receptor ratio in cells derived from human atherosclerotic lesions. Conversion from an antiproliferative to profibrotic response to TGF-beta1. 867 33


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