Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of native LDL and Ox-LDL and HDL on endothelial cell protein C activation were examined. Ox-LDL, which is postulated to contribute to cardiovascular disease, markedly suppressed activation of protein C, an important vascular anticoagulant activity. This effect was seen with both human venous and arterial endothelial cells. Endothelial cells modified LDL to a form that reduced protein C activation, an effect prevented by the anti-oxidant, probucol. Endothelial cells are known to express the acetyl LDL (scavenger) receptor, which binds chemically modified and Ox-LDL. The effect of Ox-LDL on protein C activation does not appear to result from uptake via the acetyl LDL receptor, since a known scavenger receptor antagonist (fucoidin) did not inhibit the oxidized LDL effect. In contrast to the results with Ox-LDL, native LDL and both native and oxidized HDL increased protein C activation. These data indicate that native and modified lipoproteins regulate blood coagulation by affecting vascular anticoagulant activity and suggest mechanisms that may link modified lipoproteins with both vascular disease and thrombosis.
 ...
PMID:Regulation of endothelial cell protein C activation by native and oxidized low density lipoprotein. 157 12

Endothelial cells form the luminal vascular surface and thus have a central role in the regulation of coagulation. One important way in which endothelial cells control the clotting system is by regulating the expression of binding sites for anticoagulant and procoagulant factors on the cell surface. In the quiescent state, endothelial cells maintain blood fluidity by promoting the activity of numerous anticoagulant pathways, including the protein C/protein S pathway. After activation, as can be brought about by cytokines, the balance of endothelial properties can be tipped to favor clot formation through coordinated induction of procoagulant and suppression of anticoagulant mechanisms. Tumor necrosis factor suppresses the endothelial anticoagulant cofactor thrombomodulin and induces expression of the procoagulant cofactor tissue factor. Working in concert, these changes can allow fibrin formation to proceed in an inflamed focus but maintain blood fluidity in the surrounding area of normal vasculature. Recent studies suggest that similar changes in endothelial coagulant properties can be induced by advanced glycosylation end products, proteins modified by glucose that accumulate in the vasculature at a rapid rate in diabetic subjects, indicating the potential relevance of these mechanisms in diabetic vascular disease.
 ...
PMID:Endothelium and regulation of coagulation. 206 Apr 25

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.
 ...
PMID:Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. 206 93

The influence of a disturbed hemostasis as one of the causes of retinal or ciliary vascular occlusions is still controversial. Antithrombin III, protein C and its cofactor protein S were investigated in 25 patients; 14 of them with a retinal vein occlusion, five showed an occlusion of retinal arteries and six of ciliary arteries. Patients with a preceding thromboembolic disease were excluded from the investigations. The mean values (+/- SEM) of antithrombin III (12.1 IU/ml +/- 0.4), protein C (116% +/- 4), total protein S (102% +/- 3) and free protein S (46% +/- 2) were equivalent to the mean values of a normal population. Neither does a defect or a lack of coagulation inhibitors have an essential influence on the development of an isolated retinal or ciliary vascular occlusion nor does the local occlusive vascular disorder influence the activity of systemic inhibitors.
 ...
PMID:[Inhibitors of blood coagulation in vascular occlusion of the retina and optic nerve]. 214 89

The present prospective follow-up study was made to study the effect of glycaemic regulation on levels of factor VII, protein C and protein S in 15 insulin-dependent diabetic patients without manifestations of vascular disease. Patients were tested before and after 8 weeks of 'metabolic' intervention, whereby a near-normoglycaemic state was achieved. At baseline, values of cross-linked fibrin degradation products (XL-FDP) and levels of 'total' protein S were significantly increased and protein C values were decreased in the diabetic patients when compared to control subjects, whereas levels of factor VII and 'free' protein S were near normal. After 'metabolic' intervention a decrease of all haemostatic parameters were recorded, however XL-FDP levels did not decline to control levels and the imbalance of factor VII and protein C persisted. When patients with newly diagnosed diabetes (n = 8) were compared to those with long-term disease (n = 7) higher levels of factor VII, protein C and protein S were recorded in the latter group before and after metabolic intervention; at baseline the differences reached statistical significance for factor VII and protein S, and remained significant for factor VII after metabolic intervention. Before and after intervention XL-FDP levels were higher in patients with newly diagnosed disease than in patients with long-term diabetes. The correlation analysis revealed positive correlations of factor VII, protein C and protein S to cholesterol and triglycerides, of protein S to all glycaemic control parameters, negative correlations of protein C to glucose, and of XL-FDP to factor VII, protein C and protein S. The results indicate an imbalance of haemostasis towards thrombophilicity in insulin-dependent diabetic patients, not completely correctable by glycaemic control.
 ...
PMID:The effect of near-normoglycaemic control on plasma levels of coagulation factor VII and the anticoagulant proteins C and S in insulin-dependent diabetic patients. 253 36

In view of the known association of vascular disease with increasing age, we have conducted an analysis of hemostatic system activity with respect to perturbations induced by aging phenomena. We have utilized an immunochemical assay for prothrombin fragment F1 + 2 to quantify Factor Xa activity upon prothrombin in the plasma of 199 healthy males between the ages of 42 and 80. The levels of F1 + 2 in this population generally increased as a function of age (P less than 0.0001). The metabolic behavior of this marker was determined in 10 individuals greater than 65 yr of age with varying levels of F1 + 2, which ranged from 1.28 to 5.85 nM. The elevations in the concentration of this component were not due to diminished clearance of the fragment. Radio-immunoassays for fibrinopeptide A (FPA) and the protein C activation peptide (PCP) were subsequently employed to measure thrombin activity upon fibrinogen and thrombin-thrombomodulin activity upon protein C, respectively, in 82 members of this population ranging in age from 42 to 80. Significant positive correlations were again observed between increasing age and the level of F1 + 2 (P less than 0.0001) as well as FPA (P less than 0.01) and PCP (P less than 0.002). The results of this cross-sectional study indicate that many apparently normal males of increasing age with normal immunologic levels of antithrombin III and protein C exhibit a biochemical defect that denotes the presence of an acquired prethrombotic state.
 ...
PMID:Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study. 282 64

With the continued accumulation of clinical and animal studies, it is becoming abundantly clear that the protein C anticoagulant pathway plays a critical role in the regulation of coagulation. Investigations also indicate that this pathway is intimately involved in the interaction of the coagulation and inflammatory systems. Although no direct information is presently available, the function of this pathway is likely depressed in the regions of atherosclerotic plaque. It is clear that monocytes accumulate in this region and release many growth factors and monokines that are capable of endothelial function perturbation. Perturbation of the protein C anticoagulant pathway is one viable mechanism for the hypercoagulable state in this disease. As indicated here, the endothelial cells of the vessel wall play a critical role in the initiation, and possibly expression, of this pathway. Any injury to these cells that affects the proper expression of thrombomodulin, synthesis of protein S, or Factor Va inactivation complex formation could potentially lead to a hypercoagulable state and thrombotic complications. As has been discussed, several inflammatory mediators are already known that fulfill the criteria of endothelial cell perturbants that may lead to such a state. What other entities might have similar effects, either directly or indirectly through induction of cytokines, is not known at this time. A more complete understanding of this critical pathway and the effects of vascular disease on it should lead to a better understanding of many diverse disease processes and potential therapeutic strategies in the future.
 ...
PMID:Protein C and the endothelium. 284 10

The protein C anticoagulant pathway provides many new insights into control mechanisms for regulating coagulation. The observation that protein C deficiency is associated with thrombotic tendencies in the heterozygote (106-109) and early, lethal thrombosis in the homozygote (110, 111) points to the importance of the system as a major regulatory pathway. The complexity of the system has only recently begun to emerge. Thrombin activation of protein C at the endothelial cell surface requires not only the synthesis of thrombomodulin but the coupling of the receptor to a protein C binding site. It is reasonable to assume that an inherited or acquired deficiency in thrombomodulin might lead to thrombotic tendencies. This aspect of the system may explain, in part, the association between vascular disease and thrombosis. Once activated, protein C has an almost total dependence on protein S to express anticoagulant activity. (98) This suggests that deficiencies of protein S may also be associated with thrombotic tendencies. Protein S offers an additional intriguing property. Protein S, a regulatory protein of the coagulation system, is found both free and associated with C4BP, a regulatory protein of the complement system. The high affinity, very stable interaction between these components (85) suggests that the interaction is likely to be involved in regulation. (89) The importance of the interaction remains to be demonstrated, but clearly this is a potential direct link between major control proteins of the coagulation and complement system. Clinical studies suggest that protein C and/or thrombomodulin might be effective therapeutically. Certainly, protein C supplementation during the onset of oral anticoagulant therapy would be expected to circumvent the transient rapid decrease in protein C levels that may influence the early effectiveness of oral anticoagulants. (119) In addition to the systems clinical importance, protein C, its activation, and its function offer a variety of intriguing biochemical problems. For instance, how does thrombomodulin alter the specificity of thrombin? What is the protein C binding site on the cell surface, and what role does Factor Va or its degradation products play in the formation and regulation of this site? How does protein S facilitate activated protein C anticoagulant activity and what roles do membrane surfaces play in this system? What role does beta-hydroxyaspartic acid play in protein C activation and function? How does activated protein C influence fibrinolytic activity? The answers to these questions will undoubtedly add to our understanding of the fundamental mechanisms involved in regulating blood coagulation.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Protein C. 609 83

The authors investigated the behaviour of some markers of the haemostatic balance in a group of patients with acute focal cerebral vasculopathy. The series consists of 70 female patients (mean age: 61 +/- 5), 25 of whom suffering from TIA and 45 from thrombotic stroke; 40 normal controls (mean age 43 +/- 5) were also considered. For each patient after an overnight fasting a withdrawal of venous blood was done within 24-36 hours after the admission. For each sample the determination of seven prothrombotic markers [(fibrinogen (F), factor VII (F VII), antithrombin III (AT III), protein C (PC), protein S (PS) (coagulometric method IL), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) (ELISA method Boehringer)] and of three prethrombotic markers [(fibrinopeptide A (FPA), beta-thromboglobulin (BTG) and D-dimer (D-D) (ELISA method, Boehringer)] was performed. The results obtained in the group of the cerebrovasculopathic patients compared to the controls showed a significant increase of F (p < 0.001), F VII (p < 0.005), BTG (p < 0.05) and D-D (p < 0.01), whereas significant differences regarding AT III, PC, PS, t-PA, PAI and FPA were not observed. The authors hypothesized that the increased levels of fibrinogen and factor VII in the cerebrovascular subjects, globally considered, may depend on a marked prothrombotic state, linked in a pathogenetic sense to the vascular disease; the existence of a prethrombotic state is also documented by the increase of betathromboglobulin and D-dimer.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Haemostatic balance in patients with acute focal cerebral vasculopathy. 760 35

Diabetes mellitus is associated with disturbances of the hemostatic system, which might contribute to the development of diabetic vascular disease. We investigated the effect of metabolic improvement by insulin therapy on the haemostatic system in 61 patients with type 2 diabetes mellitus and secondary sulfonylurea failure compared with 45 healthy control subjects matched for age, sex and BMI. Median age was 65, median diabetes duration 10 years. Median HbA1c (10%) and fructosamine (4.0 mM) levels were elevated before induction of therapy and decreased significantly within 6 months of insulin treatment to 7.5% and 3.0 mM, respectively (p < 0.0001). Compared with control subjects, median plasma levels of fibrinogen (317 vs 286 mg/dl), coagulation factor VII activity (1.1 vs 0.89 U/l), von Willebrand factor (1.6 vs 1.3 U/l), D-dimer (105 vs 86 micrograms/l), protein C:Ag (1.24 vs 0.95 U/l), total protein S:Ag (1.15 vs 0.91 U/l), and antithrombin III activity (1.17 vs 1.08 U/l) were significantly elevated. Levels of free protein S were not different from control values. No significant decline of coagulation parameters could be recorded during insulin therapy. Patients with diabetic vasculopathy had higher levels of D-dimer than those without (133 vs 76 micrograms/l before, 109 vs 88 micrograms/l during therapy), whereas the other haemostatic parameters were not different. Our data indicate a significant activation of the coagulation system in diabetic patients with secondary failure to sulfonylurea drugs, with signs of a prethrombotic state and endothelial cell disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Haemostatic abnormalities persist despite glycaemic improvement by insulin therapy in lean type 2 diabetic patients. 858 33


1 2 3 4 5 Next >>