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PubMed1990

Changes in and partial identification of the plasminogen activator and plasminogen activator inhibitor systems during ovarian follicular maturation in the pig.

Plasminogen, plasmin, and plasminogen activator (PA) activities and PA and PA inhibitor (PAI) contents were measured in granulosa (GC) and theca interna cell extracts and follicular fluid (FF) obtained from preovulatory follicles of prepubertal gilts treated with eCG and hCG to induce follicular growth and ovulation. Plasmin activity in FF increased just before the time of expected ovulation. This increase was not attributable to changes in plasminogen levels, which remained relatively constant during preovulatory follicular development. The increase in follicular plasmin levels was associated with significant (p less than 0.01) increases in PA activity and content and decreases in PAI content in GC and FF. Western blot analysis suggested that follicular PA activity was represented principally by two forms of tissue type PA (t-PA) each with a pI of 7.8 and with molecular masses of 72,000 and 78,000 daltons, respectively. Two PA-PAI complexes of 126,000 and 130,000 daltons were observed. These complexes were partially dissociated with nucleophilic agents into two t-PA-like forms and a 52,000-dalton PAI protein with a pI of 4.8. Biochemical characteristics of the PAI protein suggest that it belongs to the same class of inhibitors as bovine and human PAI-1. These data indicate that rupture of the porcine ovarian follicle is temporally associated with a net increase in PA activity and an increase in plasmin activity. The increase in PA activity appears to be regulated by changes in PA and PAI content.

Animals↗
PubMed1996

Presence of urokinase plasminogen activator and plasminogen activator inhibitor-1 messenger ribonucleic acids in rat endometrium during decidualization in vivo.

Rat endometrial stromal cells undergoing decidualization in vitro secrete urokinase-type plasminogen activator (uPA), and this secretion is regulated by prostaglandin E2. The present study was undertaken to determine whether uPA and plasminogen activator inhibitor-1 (PAI-1) mRNAs are expressed in vivo in the decidua of pregnant rats and in the deciduoma of "pseudopregnant" rats. Total RNA was prepared from nondecidualized and decidualized endometrial tissues at various stages of early pregnancy and examined by Northern blot analysis using specific cDNA probes for rat uPA and PAI-1. There was little uPA mRNA in the endometrium during the first 5 days of pregnancy (Day 1 = the presence of sperm in the vagina). A high level of uPA mRNA was detected on Day 7, and it declined thereafter. There was a gradual increase in PAI-1 mRNA in the decidua from Day 7 of pregnancy, reaching a peak level on Day 15 when the decidua was transformed into the maternal placenta. (RNA was not analyzed beyond Day 15 of pregnancy in this study.) In situ hybridization studies verified that uPA mRNA was present in the decidua adjacent to the implanting embryo on Day 7. Plasminogen activator inhibitor-1 mRNA was scattered in the decidualized endometrium, but greater amounts of PAI-1 mRNA were found in the fetal tissue on Day 10 of pregnancy. Northern blot analysis of RNA from the deciduoma produced in ovariectomized, steroid-treated rats by intrauterine injection of oil demonstrated a similar temporal pattern of expression of uPA mRNA; i.e., the level of uPA mRNA was highest on Day 7 and decreased thereafter. The level of PAI-1 mRNA in deciduoma was not detectable by Northern blot technique during the first 10 days of pseudopregnancy. These findings confirm that uPA mRNA is present in vivo in rat decidual cells, independent of the presence of a conceptus. By contrast, the level of PAI-1 mRNA in the uterus is probably influenced by the presence of the conceptus.

Animals↗
PubMed1997

The interaction of recombinant tissue type plasminogen activator and recombinant plasminogen activator (r-PA/BM 06.022) with human endothelial cells.

The Escherichia coli-expressed recombinant plasminogen activator (r-PA) comprising the kringle 2 and protease domains of human tissue-type plasminogen activator (t-PA) has a four-fold longer half-life time in the circulation than t-PA, possibly resulting in an increased opportunity for r-PA to interact with the endothelial lining. In the present study we investigated the interaction of r-PA and t-PA with human umbilical vein endothelial cells (HUVEC). Specific binding of 125I-t-PA and 125I-r-PA were similar at 4 degrees C (Kd 6 nmol/l; Bmax about 120 fmol/mg cell protein). About half of the specific binding sites were shared by t-PA and r-PA, because unlabeled t-PA and r-PA competed equally with 125I-labeled t-PA and r-PA for binding to HUVEC. The low affinity interaction of 125I-t-PA was several-fold higher than that of 125I-r-PA. When PA binding was studied at 37 degrees C, HUVEC bound more t-PA than r-PA to both specific and non-specific binding sites. Both t-PA and r-PA were internalized and degraded, but t-PA internalization proceeded more efficiently than that of r-PA. In the presence of 100 microM chloroquine, the degradation of t-PA and r-PA was inhibited by 75% and 40%, respectively, indicating lysosomal degradation. When the active sites of t-PA and r-PA were blocked by PPACK, part of the cell association and most of the degradation of both t-PA and r-PA were inhibited. This points to plasminogen activator inhibitor-1 (PAI-1) as one of the specific binding sites. A possible role of LDL-receptor related protein (LRP) or related members of this receptor family was investigated by using the 39 kD receptor associated protein (RAP) which prevents interaction of ligands with these receptors. RAP reduced the association of 125I-t-PA by 25% and the degradation of 125I-t-PA and 125I-r-PA by 65% and 50%, respectively. Our data show that both t-PA and r-PA bind to HUVEC and can subsequently be internalized and degraded. However, r-PA interacts less effectively with HUVEC than t-PA. This indicates that binding to the endothelium does not prevent the clearance of r-PA and is not the cause of its long half-life.

Binding Sites↗
PubMed2003

Profound imbalance of pro-fibrinolytic and anti-fibrinolytic factors (tissue plasminogen activator and plasminogen activator inhibitor type 1) and severe bleeding diathesis in a patient with cirrhosis: correction by liver transplantation.

A 49-year-old male with alcoholic cirrhosis suffered several spontaneous, life-threatening, deep muscle bleeding episodes. Laboratory evaluation indicated excessive fibrinolysis with low plasminogen, low alpha2-antiplasmin, undetectable plasminogen activator inhibitor type 1 (PAI-1) activity, high tissue plasminogen activator (t-PA) activity and high t-PA antigen. Treatment with oral anti-fibrinolytic agents prevented further bleeding episodes. Decompensated cirrhosis eventually necessitated orthotopic liver transplantation. Post-operatively, the patient did not require oral anti-fibrinolytic agents, and there were no significant bleeding events. Circulating PAI-1 activity, t-PA activity and antigen normalized by 3 months post transplant. In short, the profound bleeding diathesis, as well as the imbalance in t-PA and PAI-1 levels, corrected after liver transplantation. Recognition of such patients is important, because the bleeding diathesis is an indication rather than a contraindication for orthotopic liver transplantation.

Hemorrhagic Disorders↗
PubMed1994

The effect of various contrast media on the activation of plasminogen by streptokinase or recombinant tissue plasminogen activator in vitro.

RATIONALE AND OBJECTIVES: Radiologic contrast media (CM) may influence processes of coagulation and fibrinolysis. In the current study, the effects of various CM on the formation of plasmin were examined in an in vitro buffer system. METHODS: The effects of three clinically relevant concentrations of seven different iodine-containing CM and gadolinium-DTPA on streptokinase (SK) or recombinant tissue plasminogen activator (rt-PA)-induced plasmin formation was monitored using a plasmin-sensitive chromogenic substrate. RESULTS: Contrast media generally had an inhibitory effect at the plasminogen activation step; this effect was particularly noticeable with the ionic CM. CONCLUSIONS: Contrast media influence plasminogen activation by SK and rt-PA in vitro. Ionic CM have a more pronounced inhibitory effect than the nonionic media. The ionic Gd-DTPA shows a less inhibitory effect than the ionic iodine-containing CM. However, they must be regarded separately because of the different chemical composition of the magnetic resonance imaging and x-ray CM.

Contrast Media↗
PubMed2002

Roles of the plasminogen activator streptokinase and the plasminogen-associated M protein in an experimental model for streptococcal impetigo.

Primary infection by group A streptococci (GAS) takes place at either the throat or skin of the human host, often leading to pharyngitis or impetigo, respectively. Many GAS strains differ in their preference for throat and skin tissue sites. Previous epidemiological findings show that many of the strains displaying strong tropism for the skin have a high-affinity binding site for plasminogen, located within M protein (PAM), a prominent surface fibril. Plasminogen bound by PAM interacts with streptokinase, a plasminogen activator secreted by GAS, to yield bacterial-bound plasmin activity. In this study, PAM and streptokinase were tested for their roles in infection using an experimental model that closely mimics human impetigo. Inactivation of genes encoding either PAM or streptokinase led to a partial, but significant, loss of virulence in vivo, as measured by net growth of the bacteria and pathological alterations. The relative loss in virulence in vivo was greater for the streptokinase mutant than for the PAM mutant. However, the PAM mutant, but not the streptokinase mutant, displayed a partial loss in resistance to phagocytosis in vitro. The combined experimental and epidemiological data provide evidence that PAM and streptokinase play a key role in mediating skin-specific infection by GAS. In addition, secreted cysteine proteinase activity due to SpeB leads to degradation of streptokinase in stationary phase broth cultures. Since SpeB is also a determinant of tissue-specific GAS infection at the skin, direct interactions between these two proteolytic pathways may constitute an important pathogenic mechanism. An integrated model for superficial infection at the skin is presented.

Animals↗
PubMed1990

Transforming growth factor-beta modulates plasminogen activator activity and plasminogen activator inhibitor type-1 expression in human keratinocytes in vitro.

Transforming growth factor beta (TGF-beta) is a multifunctional mediator with effects on cellular growth, differentiation, and extracellular matrix (ECM) metabolism. Because TGF-beta stimulates fibronectin expression in cultured human keratinocytes, we wished to determine whether it might also affect ECM degradation through the plasminogen activator (PA)-plasminogen activator inhibitor (PAI) system. Immunofluorescence of human keratinocytes using a monospecific antiserum to type 1 PAI (PAI-1) showed enhanced cellular and ECM staining when they were cultured in the presence of TGF-beta. The antiserum also identified an Mr 50,000 protein in conditioned media that was markedly enhanced by TGF-beta. A corresponding stimulation of PAI-1 mRNA was demonstrated by quantitative RNA blot analysis. Total plasminogen activating activity of conditioned medium was markedly decreased by TGF-beta. Zymography showed this to be at least partially due to decreased secreted urokinase activity. TGF-beta may play an important role in stabilizing the provisional matrix synthesized by keratinocytes in healing wounds.

Cells, Cultured↗
PubMed1991

Effect of retinoic acid on the synthesis of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in human endothelial cells.

The synthesis of plasminogen activators and inhibitors in endothelial cells is highly regulated by hormones, drugs and growth factors. The present study evaluates the effect of retinoic acid on the synthesis of tissue-type plasminogen activator (t-PA) and of plasminogen activator inhibitor-1 (PAI-1) by cultured human umbilical vein endothelial cells (HUVEC). Retinoic acid produced a time- and concentration-dependent increase in the secretion of t-PA-related antigen but not of PAI-1 related antigen into the culture medium. A maximal sevenfold increase of t-PA antigen after 24 h was observed with 10 microM and a half-maximal increase with 0.1 microM retinoic acid. Retinoic acid induced a time-dependent increase of the t-PA mRNA, with a maximum at 8 h and returning to normal at 24 h. The protein kinase inhibitor H7 decreased the t-PA antigen induced by both retinoic acid and phorbol 12-myristate 13-acetate. These results suggest that treatment of HUVEC with retinoic acid increases t-PA production by a pathway which, at some level, involves protein kinases. Thus, retinoic acid induces t-PA synthesis in the absence of altered PAI-1 synthesis, which may enhance the fibrinolytic potential of the endothelium.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Transient and cell-specific expression of tissue-type plasminogen activator and plasminogen-activator-inhibitor type 1 results in controlled and directed proteolysis during gonadotropin-induced ovulation.

Proteolytic activity generated by the plasminogen-activator system (PA system) is associated with many biological processes. However, it is not known how the proteolytic activity is regulated in vivo in order to obtain directed proteolysis while, at the same time, protecting unrestrained tissue destruction. Using gonadotropin-induced ovulation as a model, we have studied how two components of the PA system, tissue-type plasminogen activator (tPA) and plasminogen-activator-inhibitor type 1 (PAI-1), are regulated temporally and spatially by gonadotropins, leading to the initiation and termination of a well-directed proteolytic process. In-situ hybridization and in-situ zymography were used to analyze the expression of tPA and PAI-1 mRNA and PA-activity in specific ovarian cell types. Both tPA and PAI-1 were found to be regulated and to have a distinct expression pattern in different ovarian compartments. tPA was expressed in both granulosa and thecal-interstitial cells; the highest levels of tPA mRNA were found in the granulosa cells of preovulatory follicles, just prior to ovulation. Consistent with a role for luteinizing hormone/chorionic gonadotropin (LH/CG) in triggering ovulation, the cells and follicles that actively expressed tPA also contained high levels of LH-receptor mRNA while cumulus cells that contain undetectable amounts of tPA mRNA were devoid of LH-receptor expression. The highest levels of PAI-1 mRNA were found about 6 h before ovulation and mainly in the thecal-interstitial cells and ovarian stroma tissue which encapsulate the follicle. Preovulatory follicles, protruding onto the surface of the ovary with less surrounding stroma tissue, expressed less PAI-1 compared to small non-ovulatory follicles embedded in inner part of the ovary. In-situ zymography also revealed that the PA activity was colocalized to the surface of the ovary just prior to ovulation. Our studies suggest that a proteolytic activity provided by tPA and modulated by PAI-1 is responsible for a controlled and directed proteolysis leading to rupture of selected follicles during ovulation.

Animals↗
PubMed1997

Type-1 plasminogen-activator inhibitor -- conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility.

We have analysed the susceptibility of latent, active, reactive-centre-cleaved and plasminogen-activator-complexed type-1 plasminogen-activator inhibitor (PAI-1) to the non-target proteinases trypsin, endoproteinase Asp-N, proteinase K and subtilisin. This analysis has allowed us to detect conformational differences between the different forms of PAI-1 outside the reactive-centre loop and beta-sheet A. Proteinase-hypersensitive sites were clustered in three regions. Firstly, susceptibility was observed in the region around alpha-helix E, beta-strand 1A, and the flanking loops, which are believed to form flexible joints during movements of beta-sheet A. Secondly, hypersensitive sites were observed in the loop between alpha-helix I and beta-strand 5A. Thirdly, the gate region, encompassing beta-strands 3C and 4C, was highly susceptible to trypsin in latent PAI-1, but not in the other conformations. The digestion patterns differed among all four forms of PAI-1, indicating that each represents a unique conformation. The differential proteolytic susceptibility of the flexible-joint region may be coupled to the differential affinity to vitronectin, binding in the same region. The analysis also allowed detection of conformational differences between reactive-centre-cleaved forms produced under different solvent conditions. The digestion pattern of plasminogen-activator-complexed PAI-1 was different from that of active PAI-1, but indistinguishable from that of one of the reactive-centre-cleaved forms, as the complexed and this particular cleaved PAI-1 were completely resistant to all the non-target proteinases tested. This observation is in agreement with the notion that complex formation involves reactive-centre cleavage and a large degree of insertion of the reactive-centre loop into beta-sheet A. Our analysis has allowed the identification of some flexible regions that appear to be implicated in the conformational changes during the movements of beta-sheet A and during the inhibitory reaction of serpins with their target proteinases.

Binding Sites↗
PubMed1994

Calcium modulates the expression of urokinase plasminogen activator and plasminogen activator inhibitor 2 by human keratinocytes.

Keratinocytes propagated in low calcium (30 microM CaCl2) serum-free media grow in a monolayer and exhibit morphologic and biosynthetic phenotypes most similar to those of keratinocytes in the basal layer of the normal epidermis. When the calcium in the media is elevated to 1 mM, the cells stratify and differentiate. The effects of calcium on human foreskin keratinocyte expression of urokinase type (uPA) and tissue type (tPA) plasminogen activator enzymes and plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2) were assessed by Northern analyses. Our data show that keratinocytes, cultured in the presence of low and high CaCl2 concentrations, express transcripts for uPA and PAI-2. Message levels for uPA were dramatically reduced in cultures stimulated with calcium, whereas those for PAI-2 were only slightly decreased. Little PAI-1 mRNA and no tPA mRNA were detected, independent of calcium levels. Actin mRNA levels were not modulated consequent to calcium stimulation. Hybridizations to 28S ribosomal RNA confirmed that equal amounts of RNA were analyzed from cells grown under low and high calcium conditions. These data demonstrate that keratinocytes, propagated in serum-free media under low and high calcium conditions, are similar to normal human epidermis with respect to their expression of regulators of plasminogen activation. Additionally, they suggest that the ratio of PAI-2 to uPA increases with keratinocyte differentiation.

Blotting, Northern↗
PubMed1988

Comparison of kinetic parameters of the activation of Glu-plasminogen by tissue plasminogen activator obtained from various sources.

Kinetic analyses were made for the activation of Glu-plasminogen (Glu-Plg) by tissue plasminogen activator (t-PA) obtained from various sources. We compared kinetic parameters for three t-PA preparations. t-PA(M) was obtained from cultured melanoma cell line, and t-PA(W) and t-PA(TD) were obtained from cells with recombinant DNA. t-PA(W) had two chains whereas t-PA(TD) had one chain. Although values of kinetic parameters were different in the three t-PA preparations, there were following general tendencies. The presence of catalytic amounts of fibrin resulted in a decrease in Km, whereas the presence of larger amounts of fibrin resulted in an increase in kcat with a slight decrease in Km. The presence of fibrinogen also enhanced the activation of Glu-Plg by t-PA with an increase in kcat and without change in Km. When the effects of fragment D or E were compared, the presence of increasing amounts of E resulted in an increase in kcat, but the presence of increasing amounts of D resulted in an increase in kcat and a decrease in Km. The results suggest that roles of D and E domains of fibrin may be different in the enhanced activation of plasminogen by t-PA.

Animals↗
PubMed1990

Changes in plasminogen activator inhibitor 1 and tissue-type plasminogen activator during exercise in patients with coronary artery disease.

As depressed fibrinolysis is implicated in the pathogenesis of coronary artery disease, we have studied the activation of fibrinolysis during maximal, symptom-limited exercise in a group of 68 men. After exercise they were divided, according to their coronary angiography and exercise 201Tl emission computed tomography results, into three groups. Group 1: persons with normal exercise 201Tl emission computed tomography results and no underlying diseases who served as controls; group 2: patients with coronary artery disease without exercise-induced myocardial ischemia, and group 3: patients with coronary artery disease with transient, exercise-induced myocardial ischemia. Before and at peak exercise we measured the plasminogen activator activity (PAA) in the euglobulin fraction of plasma by an amidolytic method and the concentrations of tissue plasminogen activator (t-PA), activator-inhibitor complex - plasminogen activator inhibitor 1 (PAI-1) complexed with t-PA - and total PAI-1 by enzyme immunoassay. The concentration of free PAI-1 in plasma was calculated by subtraction of the concentration of activator-inhibitor complex from that of total PAI-1. Under basal conditions, group 3 had significantly higher free and total PAI-1 levels than group 1. There were no statistically significant differences between the three groups in PAA, t-PA, and activator-inhibitor complex levels. At peak exercise, group 1 showed the highest release of t-PA accompanied with highest increases in PAA as well as in activator-inhibitor complex, the proportion of released t-PA antigen not bound to PAI-1 being highest in group 1. Free PAI-1 decreased significantly, but there were no differences between individual groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Ultrasound affects distribution of plasminogen and tissue-type plasminogen activator in whole blood clots in vitro.

Ultrasound of 2 MHz frequency and 1.2 W/cm(2) acoustic intensity was applied to examine the effect of sonication on recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis as well as on the distribution of plasminogen and t-PA within whole blood clots in vitro. Thrombolysis was evaluated quantitatively by measuring clot weight reduction and the level of fibrin degradation product D-dimer (FDP-DD) in the supernatant. Weight reduction in the group of clots treated both with ultrasound and rt-PA was 35.2% +/-6.9% which is significantly higher (p<0.0001) than in the group of clots treated with rt-PA only (19.9% +/-4.3%). FDP-DD level in the supernatants of the group treated with ultrasound and rt-PA increased sevenfold compared to the group treated with rt-PA alone, (14895 +/-2513 ng/ml vs. 2364 +/-725 ng/ml). Localization of fibrinolytic components within the clots was accomplished by using gel-entrapping technique and immunohistochemistry. Spatial distributions of t-PA and plasminogen showed clearly that ultrasound promoted the penetration of rt-PA into thrombi significantly (p<0.0001), and broadened the zone of lysis from 8.9 +/-2.6 microm to 21.2 +/-7.2 microm. We speculate that ultrasound enhances thrombolysis by affecting the distribution of rt-PA within the clot.

Fibrinolysis↗
PubMed1992

Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor.

BACKGROUND: Although isolated abnormalities of plasminogen activation and inhibition have been reported among selected patients with venous thrombosis, it is unclear whether these deficiencies of fibrinolysis are important risk factors for thromboembolic disease. METHODS AND RESULTS: To evaluate whether baseline levels of endogenous tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) predict the future occurrence of venous thrombosis, levels of these proteins were measured in prospectively collected plasma samples from 55 participants in the Physicians' Health Study who later developed deep venous thrombosis or pulmonary embolism and from an equal number of age- and smoking-matched control subjects who remained free of vascular disease during a mean follow-up period of 60.2 months. Overall, there were no statistically significant differences between case patients and control subjects in baseline levels of PAI-1 (50.5 versus 59.5 ng/ml, p = 0.26), t-PA (13.4 versus 13.3 ng/ml, p = 0.94), or PAI-1:t-PA ratio (6.84 versus 6.58, p = 0.82). No evidence of a threshold effect or trend was seen when these data were analyzed by increasing quartiles of PAI-1 (p = 0.73), t-PA (p = 0.62), or PAI-1:t-PA ratio (p = 0.93). These results were unchanged after multivariate analysis that simultaneously controlled for other baseline cardiovascular risk factors. CONCLUSIONS: In contrast to previous uncontrolled case series and smaller retrospective studies, these prospective data provide strong evidence that baseline fibrinolytic state, as measured by t-PA and PAI-1, does not predict the occurrence of future venous thrombosis.

Adult↗
PubMed1994

Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells.

BACKGROUND: The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway. METHODS AND RESULTS: The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity. CONCLUSIONS: Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.

Amino Acids↗
PubMedDate not supplied

The prognostic value of vascular endothelial growth factor, urokinase plasminogen activator and plasminogen activator inhibitor-1 in node-negative breast cancer.

The vascular endothelial growth factor (VEGF) and the plasminogen activator system play an essential role in solid tumor angiogenesis and in tumor invasion and metastasis. In the present study we investigated the relationship between patient outcome and levels of VEGF, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor cytosols of 196 node-negative primary invasive breast cancer patients who did not receive any adjuvant therapy. The median follow-up was 65 months. VEGF, uPA and PAI-1 were measured by commercially available enzyme-linked immunosorbent assays. Cox's univariate analysis showed that pT (p = 0.0007), uPA (p = 0.0156) and PAI-1 (p = 0.0015) had a significant impact on relapse-free survival, whereas VEGF did not have any prognostic value (p = 0.18). Bivariate analysis showed significant interactions between uPA and PAI-1 (p = 0.0035) and between VEGF and PAI-1 (p = 0.006). Our study confirms that uPA and PAI-1 cytosol levels can be considered as prognostic factors for relapse-free survival in node-negative breast cancer. Moreover, the interaction between VEGF and PAI-1 warrants further investigation into the relationship between the biomarkers of angiogenesis and those of the protease cascade.

Adult↗
PubMed2006

Prognostic significance of urokinase plasminogen activator and plasminogen activator inhibitor-1 mRNA expression in lymph node- and hormone receptor-positive breast cancer.

BACKGROUND: One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system that comprises of, among others, the urokinase Plasminogen Activator (uPA) and its main inhibitor, the Plasminogen Activator Inhibitor-1 (PAI-1). In this study, we investigated the prognostic value of uPA and PAI-1 at the mRNA level in lymph node- and hormone receptor-positive breast cancer. METHODS: The study included a retrospective series of 87 patients with hormone-receptor positive and axillary lymph node-positive breast cancer. All patients received radiotherapy, adjuvant anthracycline-based chemotherapy and five years of tamoxifen treatment. The median patient age was 54 and the median follow-up time was 79 months. Distant relapse occurred in 30 patients and 22 patients died from breast cancer during follow-up. We investigated the prognostic value of uPA and PAI-1 at the mRNA level as measured by real-time quantitative RT-PCR. RESULTS: uPA and PAI-1 gene expression was not found to be correlated with any of the established clinical and pathological factors. Metastasis-free Survival (MFS) and Breast Cancer specific Survival (BCS) were significantly shorter in patients expressing high levels of PAI-1 mRNA (p < 0.0001; p < 0.0001; respectively). In Cox multivariate analysis, the level of PAI-1 mRNA appeared to be the strongest prognostic factor for MFS (Hazard Ratio (HR) = 10.12; p = 0.0002) and for BCS (HR = 13.17; p = 0.0003). Furthermore, uPA gene expression was not significantly associated neither with MFS (p = 0.41) nor with BCS (p = 0.19). In a Cox-multivariate regression analysis, uPA expression did not demonstrate significant independent prognostic value. CONCLUSION: These findings indicate that high PAI-1 mRNA expression represents a strong and independent unfavorable prognostic factor for the development of metastases and for breast cancer specific survival in a population of hormone receptor- and lymph node-positive breast cancer patients.

Breast Neoplasms↗