Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.
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PMID:The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. 1067 14

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.
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PMID:Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor. 1074 20

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers share a number of common properties, including their ability to lower blood pressure. However, they can be differentiated based on their individual effects on the renin-angiotensin system, the fibrinolytic system and the actions of bradykinin. They act at different points in the cascade of events that constitute the renin-angiotensin system. In animal models of atherosclerosis, ACE inhibition was associated with a significant reduction in the percentage surface area of lesions, while no similar effect was evident with AT1 receptor blockade. In the fibrinolytic system, both ACE inhibition and AT1 receptor blockade were associated with reduced aldosterone levels, although the effect was greater with ACE inhibition; only ACE inhibition was associated with a significant reduction in plasminogen activation inhibitor-1. By blocking the degradation of bradykinin, ACE inhibitors potentiate the ability of bradykinin to reduce blood pressure and stimulate the release of tissue-type plasminogen activator from the vasculature, an effect not seen with AT1 receptor blockers.
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PMID:Pharmacology of ACE inhibitors versus AT1 blockers. 1090 25

Urokinase type plasminogen activator (uPA) may influence brain pathophysiology after injury. We studied disruption of the blood-brain barrier (BBB) and changes in the vasculature after a brain stab wound in uPA-deficient, uPA receptor-deficient, and PA inhibitor-1 (PAI-1) deficient mice. The extravasation of immunoglobulin was greater in PAI-1 deficient mice; less pronounced in uPA-deficient mice; similar to controls in uPA receptor-deficient mice. Vasculatures in the wound proliferated in PAI-1 deficient mice. Our study shows that uPA affects BBB disruption. PA enhances angiogenesis after brain injury.
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PMID:Roles of urokinase type plasminogen activator in a brain stab wound. 1113 4

Tissue plasminogen activator (tPA) promotes fibrinolysis, and impaired fibrinolysis is associated with atherosclerosis and thrombosis. Plasminogen activator inhibitor-1 (PAI-1) inhibits t-PA expression. The effects of acute laboratory stressors on tPA and tPA/PAI-1 complexes were assessed in a sample of 11 cardiac patients. Participants were randomly assigned to either a stress or relaxation condition at time 1, and the alternative condition at time 2. Blood samples were taken before (pre) and after (post) each session and participants completed a battery of psychological questionnaires. Two-way repeated-measures analysis of variance revealed a statistically significant decrease in tPA (P = 0.01) and tPA-PAI-1 complexes (P = 0.04) during the mental stress condition. Anger-in had a strong relationship to decreases in tPA/PAI-1 levels in the stress condition (r = 0.68, P < 0.05). Relaxation had no significant effect on tPA and tPA/PAI-1 levels. These data suggest that decreased fibrinolysis mediates the relationship between mental stress and atherosclerosis.
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PMID:Acute psychological stress decreases plasma tissue plasminogen activator (tPA) and tissue plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complexes in cardiac patients. 1113 73

In contrast to a reduced risk of coronary heart disease (CHD) with light to moderate alcohol consumption, heavy alcohol intake and binge drinking are associated with increased cardiovascular mortality. Alcohol has an acute and profound effect on fibrinolysis that may be relevant to the pathogenesis of CHD. The short-term effects of a low (two glasses, 250 mL, 20 g ethanol) and a high (six glasses, 750 mL, 60 g ethanol) intake of red wine were studied in male volunteers and compared to the intake of mineral water. To find a threshold for inhibition of fibrinolysis and to study a binge effect, a second experiment was performed comparing the intake of four (500 mL, 40 g ethanol) and eight (1000 mL, 80 g ethanol) glasses of red wine with mineral water. Plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), plasmin-antiplasmin (PAP) complexes and clot lysis time were measured. In contrast to the circadian rhythm with an enhanced fibrinolysis in the evening that was found in the mineral water group, an intake above four glasses of wine inhibited fibrinolysis significantly. After the intake of two glasses no significant disturbance of the circadian rhythm was observed. Five hours after the consumption of six glasses of wine, a dramatic increase occurred of PAI-1 antigen (77 +/- 42 microg L-1 vs. - 5 +/- 10 microg L-1 in the mineral water controls; P < 0.001) and PAI-1 activity (27 +/- 15 U mL-1 vs. - 2 +/- 3 U mL-1 in mineral water controls; P < 0.001). Despite a rise in t-PA antigen, t-PA activity dropped (- 0.5 +/- 0.2 U mL-1 vs. - 0.1 +/- 0.2 in controls; P < 0.001) as did PAP complexes (- 103 +/- 55 microg L-1 vs. - 26 +/- 57 microg L-1 in controls; P < 0.01). After the consumption of eight glasses of wine, the clot lysis assay indicated continued inhibition of fibrinolysis the following morning. Drinking a large amount of alcohol in the evening results in an acute inhibition of fibrinolysis, persisting the following morning. This may predispose to accelerated atherosclerosis and set the stage for thrombotic coronary events, explaining the higher cardiovascular mortality risk in binge drinkers.
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PMID:Acute inhibitory effect of alcohol on fibrinolysis. 1116 56

The aim of this study was to determine the effects of ECM protein coatings and surface modification of PTFE on the ability of seeded human endothelial cells (EC) to secrete prostacyclin (PGI2), plasminogen inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA). PTFE surfaces were modified by a novel surface modification technique based on ammonia plasma. Fibronectin, collagen type-1 and gelatin-coated ammonia plasma modified PTFE and unmodified PTFE surfaces were employed and compared in this study. All ammonia plasma modified surfaces showed similar secretions of PGI2 compared to non-modified PTFE surfaces. With the exception of gelatin-coated modified PTFE, seeded EC seeded on all modified PTFE showed lower levels of PAI-1 secretion compared to those seeded on unmodified PTFE. The specific activity of t-PA secreted by EC seeded on ammonia plasma modified and fibronectin coated modified PTFE showed increases of 100 and 30%, respectively, when compared to their unmodified counterparts. Our studies show that EC seeded on modified PTFE have ability to secrete PGI2 that modulates the early phase of thrombus formation. Furthermore, superior t-PA profile, along with lower levels of PAl-1 suggest that ammonia plasma modification and use of appropriate ECM proteins can modulate antithrombotic and fibrinolytic properties of in vitro endothelialized vascular prostheses. Accordingly, these surfaces may be suitable to further develop protocols and other strategies for arterial and venous reconstruction.
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PMID:Antithrombotic and fibrinolytic system of human endothelial cells seeded on PTFE: the effects of surface modification of PTFE by ammonia plasma treatment and ECM protein coatings. 1133 19

Previous studies have demonstrated that plasminogen activator (PA) activity is significantly high in semen of infertile men, which is also high in semen when azoospermia or oligozoospermia is induced by injection of testosterone enanthate (TE) into healthy adult men or rhesus monkeys. To further clarify the source and possible role of PA in semen, the present study was undertaken to examine: (1) whether the mRNAs for tissue type PA (tPA), urokinase type PA (uPA), and PA inhibitor-1 (PAI-1) are expressed in epididymis, seminal vesicle and prostate gland of rhesus monkeys; and (2) whether PA has some effect on in vitro sperm capacitation as judged by the potential of sperm motility, acrosome reaction (AR) and in vitro fertilization. Our results showed that (1) mRNAs for PA and PAI-1 were expressed in epididymis, seminal vesicle and prostate gland, and (2) uPA, but not tPA, improved sperm mobility, induced AR and enhanced sperm capacity to fertilize mature eggs. Thus, it is concluded that PA activity in semen comes not only from testis and epididymis, but also from seminal vesicle and prostate gland; and that uPA, but not tPA, may play a role in sperm capacitation.
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PMID:[Source of plasminogen activator in rhesus monkey semen and its possible role in sperm capacitation]. 1135 97

Several studies have shown cardiovascular benefit in treating hypercholesterolemia with HMG-CoA reductase inhibitor. However, in addition to the lowering of cholesterol, the beneficial effects of this inhibitor reflect other pharmacological activities. Whether these beneficial effects are partly mediated by changes in fibrinolytic factors remains to be proven, since clinical studies on the effects of HMG-CoA reductase inhibitors on fibrinolytic factors have not yielded consistent results. The purpose of this study was to evaluate the effects of fluvastatin on fibrinolytic factors in hypercholesterolemic patients. After 6 weeks on a low-fat, low-cholesterol diet, 23 outpatients known to have primary hypercholesterolemia with low density lipoprotein cholesterol (LDL-C) > or = 130 mg/dl with at least 2 risk factors or fasting LDL-C > or = 160 mg/dl were selected for the study. Venous blood samples were collected at baseline and at 8 weeks after fluvastatin therapy (40 mg/day) to measure of tissue plasminogen activator (t-PA), plasminogen activators inhibitor-1 (PAI-1), fibrinogen, D-dimer and lipid profile. After 8 weeks of therapy, fluvastatin reduced serum cholesterol by 11% (261.9 mg/dl vs 233.2 mg/dl, P < 0.01) and LDL-C by 22% (191.9 mg/dl vs 149.3 mg/dl, P < 0.01). D-dimer was significantly decreased (0.38 ng/L vs 0.28 ng/L, P = 0.02) and tPA, PAI-1 and fibrinogen tended to decrease after therapy. Fluvastatin therapy improved fibrinolytic profile; the result of this study may in part explain the benefit of HMG-CoA reductase inhibitor on cardiovascular system other than lipid lowering.
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PMID:The effect of fluvastatin on fibrinolytic factors in patients with hypercholesterolemia. 1139 99

The cell adhesive protein vitronectin is a common component of interstitial extracellular matrix and circulates in plasma. It competes effectively with other plasma proteins to adsorb to certain biomaterial surfaces, and is likely to represent an important cell adhesion mediator on the luminal surface of vascular grafts. It is also found associated with certain vascular pathologies. We have shown previously that human endothelial cells grow poorly on a vitronectin surface compared with other extracellular matrix molecules. In this paper we show that endothelial cells seeded on vitronectin and fibronectin produced substantially different profiles of extracellular matrix molecules. The most outstanding difference was in the amount of matrix-localised plasminogen activator-inhibitor-1 which was high on vitronectin and negligible on fibronectin. This was correlated with a small but significant inhibition of cell adhesion to vitronectin compared with fibronectin, and very significant interference with dissociation of cell: extracellular matrix contacts, resulting either from direct inhibition of the proteolytic activity of urokinase, or from interference with urokinase-receptor signaling and consequent focal adhesion turnover. Such interference would inhibit cell proliferation by disabling the cells from loosening their matrix contacts in order to proceed through mitosis. This would seriously compromise endothelial recovery in cases of damage to the vascular wall and placement of stents or grafts, where the presence of surface-adsorbed vitronectin is likely to modulate the tissue response.
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PMID:Human endothelial cells grow poorly on vitronectin: role of PAI-1. 1140 Jan 67


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