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

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160-180 mmol Na(+) and 60-80 mmol K(+), were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 +/- 0.45 ng ml(-1) h(-1) to 0.34 +/- 0.29 ng ml(-1) h(-1) (p=0.005), which returned to the baseline range at C2 (0.65 +/- 0.45 ng ml(-1) h(-1); p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 +/- 9.1 ng/ml), decreasing by 1230 hours (22.6 +/- 5.9 ng/ml), with a further decrease at 1630 hours (12.3 +/- 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.
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PMID:Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects. 1196 23

Trophoblast implantation depends, in part, on the controlled production of plasmin from plasminogen, a process regulated by plasminogen activators and plasminogen activator inhibitors. We have determined that angiotensin II (Ang II) stimulates plasminogen activator inhibitor-1 (PAI-1) synthesis and secretion in human trophoblasts in a time- and concentration-dependent manner. Our results indicate that Ang II activates PAI-1 gene expression through the AT1 receptor and involves the calcium-dependent activation of calcineurin and the nuclear translocation of NFAT. Increased PAI-1 synthesis and secretion is associated with reduced trophoblast invasion as judged by an in vitro invasion assay. These studies are the first to link the renin-angiotensin system with the fibrinolytic system to regulate trophoblast invasion.
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PMID:Angiotensin II inhibits human trophoblast invasion through AT1 receptor activation. 1198 98

Thrombus formation and degradation is partly due to a complex interplay between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1). There is accumulating evidence that plasma levels of t-PA and PAI-1 may be influenced by an interaction between the fibrinolytic and renin-angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t-PA and PAI-1 is influenced by interactive effects of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single-locus analysis, no evidence for heterogeneity of plasma t-PA and PAI-1 correlations among either ACE I/D or PAI-1 4G/5G genotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t-PA and PAI-1 correlations among multilocus ACE I/D and PAI-1 4G/5G genotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t-PA and PAI-1 may be dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. This study supports the idea that interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PA and PAI-1.
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PMID:The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. 1212 88

Regulation of vascular tone by the endothelium is abnormal in patients with heart failure and contributes to the characteristic peripheral vasoconstriction and increased afterload. This endothelial dysfunction is mediated through several endothelium-derived factors, including nitric oxide; there is an important interplay between the endothelium and the renin angiotensin system. The benefits of ACE inhibition in heart failure relate, in part, to a reduction in ischemic events which may be mediated by improvements in endothelial function and the endothelium derived fibrinolytic parameters: tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1). In addition to potential improvements in the regulation of vasomotion, ACE inhibitor therapy may increase bradykinin induced t-PA release and/or reduce angiotensin II mediated PAI-1 release. Recent evidence suggests that both angiotensin II type 1 receptor (AT(1)) antagonism and ACE inhibition improve basal fibrinolytic parameters in patients with heart failure which may facilitate the acute endogenous fibrinolytic response. 1999 by CHF, Inc.
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PMID:The renin angiotensin system and endothelial dysfunction in chronic heart failure: role of endogenous fibrinolysis. 1218 94

ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT1) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m2, or fasting serum triglyceride > or =2.8 mmol/L) hypertensive subjects (mean age, 47.9+/-2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019) pressure. Ramipril (from 133.6+/-5.1/94.5+/-2.4 to 127.0+/-3.1/91.4+/-3.3 mm Hg) or losartan (from 137.0+/-3.9/93.1+/-2.9 to 123.7+/-2.6/86.4+/-2.1 mm Hg) further reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013) but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT1 receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT1 receptor antagonism.
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PMID:ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. 1246 70

The role of proteases and of antiproteases in the progression of renal disease is well established. Most studies have focused on the serine-proteases of the plasmin/plasminogen activator system and on matrix metalloproteases. Recently, renin, an aspartyl-protease, has attracted much attention because of the role of angiotensin II in the progression of renal lesions and because of the discovery of a functional renin receptor. This receptor is a 45 kDa membrane-protein that binds specifically renin and prorenin. The binding of renin induces an increase of the catalytic efficiency of angiotensinogen conversion into angiotensin I by receptor-bound renin compared to renin in soluble phase, and a rapid phosphorylation of the receptor on serine and tyrosine residues associated with an activation of MAP kinases ERK1/2. Immunofluorescence and confocal analyses on normal human kidney and cardiac biopsies show that the receptor is localized within the mesangial area of glomeruli and in the sub-endothelium of kidney and coronary arteries, associated to smooth-muscle cells. In summary, this receptor exerts dual effects, mediating renin cellular response and increasing the efficiency of angiotensinogen cleavage by membrane-bound renin. These observations emphasizes the importance of angiotensin II generation at the cell surface and the cellular effects of renin add new dimensions (and complexity) to the classical dogma that angiotensin II is the only effector of the RAS.
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PMID:[Proteases and antiproteases in the progression of chronic renal insufficiency lesions. The role of the tissue renin-angiotensin system and the renin receptor]. 1264 96

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1+/-7.8 to 16.9+/-9.9 ng/mL at 9 am, P=0.019; from 7.6+/-5.4 to 11.5+/-7.3 ng/mL at 11 am, P=0.027; from 9.3+/-7.7 to 13.7+/-8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0+/-23.4 to 16.7+/-19.0 ng/mL at 10 am, P=0.041; from 17.5+/-21.7 to 12.7+/-16.8 ng/mL at 11 am, P=0.043; from 20.3+/-22.6 to 16.6+/-19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.
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PMID:Differing effects of mineralocorticoid receptor-dependent and -independent potassium-sparing diuretics on fibrinolytic balance. 1602 47

Essential arterial hypertension often predisposes patients to prothrombotic state and increased risk of vascular and organ complications. Vital role in regulation of hemostatic processes is played by genetic factors, renin-angiotensin system and disorders of lipid metabolism. Prime genetic factors involved in the process are 4G/5G polymorphism of promoter region coding tissue plasminogen activator inhibitor-1 (PAI-1) and I/D polymorphism for angiotensin converting enzyme (ACE) gene. The aim of work was the evaluation of alterations within fibrinolysis system (estimation of t-PA and PAI-1 levels), fibrinogen concentration (Fb) and ACE activity with regard to co-existent dyslipidemia and features of left ventricle hypertrophy (LVH). Moreover the analysis of influence of 4G/5G PAI and I/D ACE gene polymorphism on intensification of aforementioned alterations among hypertensive patients was performed. Research was carried out in 170 subjects under 40 years old, in two study groups, HT-- hypertensive group--125 patients with previously untreated hypertension without clinical features of ischaemic heart disease and NT--45 normotensive, healthy subjects. HT group has been further divided into four subgroups: DLP (dyslipidemic, n = 51), NLP (normolipidemic n = 74), LVH+ (with features of left ventricle hypertrophy, n = 35), LVH (-) (without features of left ventricle hypertrophy, n = 90). In a whole HT group significantly higher levels of PAI-1, t-PA and Fb were noted in comparison to NT group, considerably more pronounced within DLP rather than NLP subgroups. Moreover, pronounced increase in ACE activity was recorded in DLP and LVH+ subgroups. It has been proved that 4G/4G homozygous subjects of 4G/5G PAI-1 gene polymorphism from HT group tend to present higher levels of PAI-1 and t-PA if contrasted to 4G/4G genotype of NT group, with more distinct effect within DLP subgroup. Carriers of D allele (genotypes I/D, D/D) of I/D ACE gene polymorphism from HT group characterise with significantly higher activity of ACE in contrast to I/I genotype of HT group, with particularly marked effect in DLP and LVH+ subgroups. Basing on above mentioned results it may be concluded that essential hypertension (especially if complicated with dyslipidemia) impairs fibrinolysis, what might be related to renin-angiotensin system activation in lipid metabolism disorders. Deletion alleles of 4G/5G polymorphism (4G allele) and I/D polymorphism (D allele) in patients with hypertension independently modify fibrinolysis towards prothrombotic state with more distinct effect in dyslipidemia. Increased activity of ACE in D allele carriers may predispose to left ventricle hypertrophy.
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PMID:[Plasminogen activator inhibitor-1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D gene polymorphisms and fibrinolytic activity in patients with essential hypertension and dyslipidemia]. 1613 May 96

To test the hypothesis that NO contributes to effects of angiotensin-converting enzyme inhibitors on fibrinolysis, fibrinolytic balance was assessed in 17 normal subjects during placebo and after randomized, double-blind 4-week treatment with the NO precursor L-arginine (3 g TID), ramipril (10 mg QD), or L-arginine+ramipril. Neither L-arginine nor ramipril alone affected basal plasminogen activator inhibitor-1 or tissue-type plasminogen activator (t-PA) antigen in these salt-replete subjects in whom plasma renin activity was suppressed (mean+/-SD 0.7+/-0.5 ng angiotensin I/mL per hour). In contrast, L-arginine+ramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8+/-9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1:t-PA (2.3+/-1.6) compared with placebo (13.5+/-10.8 ng/mL, P=0.006; ratio 2.9+/-2.1, P=0.015) or ramipril alone (15.2+/-13.2 ng/mL, P=0.009; ratio 3.7+/-3.3, P=0.005). L-arginine and ramipril synergistically increased d-dimers (23.1+/-31.5, 29.7+/-50.0, 35.1+/-50.0, and 57.1+/-144.8 ng/mL during placebo, L-arginine, ramipril, and L-arginine+ramipril, respectively; P<0.05 for L-arginine+ramipril versus any other group). During ramipril, the NO synthase inhibitor L-NG-nitro-arginine-methyl-ester (2 mg/kg) significantly increased plasminogen activator inhibitor-antigen after 2 hours (from 9.4+/-8.6 ng/mL during vehicle to 13.5+/-11.0 ng/mL during L-NG-nitro-arginine-methyl-ester; P=0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0.4+/-0.3 to 0.5+/-0.4 IU/mL; P=0.031), consistent with an effect on release. Both effects of L-NG-nitro-arginine-methyl-ester were reversed by L-arginine. During angiotensin-converting enzyme inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance in normotensive salt-replete subjects.
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PMID:Endogenous NO regulates plasminogen activator inhibitor-1 during angiotensin-converting enzyme inhibition. 1643 54

Thrombosis is a key factor in the pathophysiology of cardiovascular disease. Important biochemical constituents of the fibrinolytic system, affecting thrombosis, include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both t-PA and PAI-1 are determined by multiple genetic and environmental factors. We aimed to investigate whether the effects of polymorphism in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on t-PA or PAI-1 levels are dependent on environmental factors in a large population-based sample from the PREVEND study in Groningen, The Netherlands (n = 2,527). We found strong evidence (P <or= 0.02) for interaction effects of polymorphisms from the bradykinin receptor (BDKRB2) gene and alcohol consumption on t-PA in females and males and on PAI-1 in males. Only suggestive evidence (P <or= 0.10) was present for an interaction effect of the BDKRB2 gene and alcohol consumption on PAI-1 levels in females. Another consistent finding was evidence for an interaction between bradykinin receptor (BDKRB2) gene polymorphisms and body size as measured by body mass index and/or waist-hip-ratio. For each gender and for both t-PA and PAI-1 there was at least one BDKRB2-body size combination that exhibited suggestive (P <or= 0.10), significant (P <or= 0.04) and/or strong evidence (P <or= 0.02) for interaction. In conclusion, the genetic architecture of t-PA and PAI-1 is dependent on the environmental context such as body size and alcohol use. The present study emphasizes the importance of including environmental factors in genetic analyses to fully comprehend the genetic architecture of a specific trait.
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PMID:The effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context. 1759 94


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