Effect Of Plasminogen Activator Inhibitor Research Articles

Specific inhibition of plasminogen activator inhibitor 1 reduces blood glucose level by lowering TNF-a

AimsThe study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism. Materials and methodsWe developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice. Key findingsPAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes. SignificanceThese findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.

SiRNA-mediated silencing of PAI-1 gene acts as a promoter over the recanalization of endothelial progenitor cells in rats with venous thrombosis.

With the changing lifestyle, venous thrombosis (VT) is becoming increasingly prevalent and poses a burden on the health economy. Endothelial progenitor cells (EPCs) are recruited into resolving VT. We aimed to investigate the effect of plasminogen activator inhibitor 1 (PAI-1) silencing on the recanalization of VT in rat EPCs. EPCs and VT rat models were cultured and treated with negative control-siRNA vector and PAI-1-siRNA vector, respectively. 4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound-healing test, and Matrigel-induced tubular experiment were performed to detect the ability of cell proliferation, migration, and EPCs lumen formation. Immunohistochemistry was used to observe the recanalization of thrombus. The messenger RNA (mRNA) and protein expression of PAI-1 and vascular endothelial growth factor (VEGF) were determined by reverse transcription quantitative polymerase chain reaction and Western blot analysis. PAI-1-siRNA enhances the luminal formation ability of EPCs and significantly promotes EPCs homing. In response to PAI-1 gene silencing, tissues from inferior vena cava displayed reduced mRNA and protein expression of PAI-1, increased VEGF expression as well as promoted lumen-like structures. PAI-1 gene silencing can promote the recanalization of VT by enhancement of the luminal formation ability of rats' EPCs.

Proteolysis of plasminogen activator inhibitor‐1 by Yersinia pestis remodulates the host environment to promote virulence

Essentials Effect of plasminogen activator inhibitor (PAI)‐1 on plague and its Y. pestis cleavage is unknown.An intranasal mouse model of infection was used to determine the role of PAI‐1 in pneumonic plague.PAI‐1 is cleaved and inactivated by the Pla protease of Y. pestis in the lung airspace.PAI‐1 impacts both bacterial outgrowth and the immune response to respiratory Y. pestis infection. Click to hear Dr Bock discuss pathogen activators of plasminogen.SummaryBackgroundThe hemostatic regulator plasminogen activator inhibitor‐1 (PAI‐1) inactivates endogenous plasminogen activators and aids in the immune response to bacterial infection. Yersinia pestis, the causative agent of plague, produces the Pla protease, a virulence factor that is required during plague. However, the specific hemostatic proteins cleaved by Pla in vivo that contribute to pathogenesis have not yet been fully elucidated.ObjectivesTo determine whether PAI‐1 is cleaved by the Pla protease during pneumonic plague, and to define the impact of PAI‐1 on Y. pestis respiratory infection in the presence or absence of Pla.MethodsAn intranasal mouse model of pneumonic plague was used to assess the levels of total and active PAI‐1 in the lung airspace, and the impact of PAI‐1 deficiency on bacterial pathogenesis, the host immune response and plasmin generation following infection with wild‐type or ∆pla Y. pestis.ResultsWe found that Y. pestis cleaves and inactivates PAI‐1 in the lungs in a Pla‐dependent manner. The loss of PAI‐1 enhances Y. pestis outgrowth in the absence of Pla, and is associated with increased conversion of plasminogen to plasmin. Furthermore, we found that PAI‐1 regulates immune cell recruitment, cytokine production and tissue permeability during pneumonic plague.ConclusionsOur data demonstrate that PAI‐1 is an in vivo target of the Pla protease in the lungs, and that PAI‐1 is a key regulator of the pulmonary innate immune response. We conclude that the inactivation of PAI‐1 by Y. pestis alters the host environment to promote virulence during pneumonic plague.

Ischaemic stroke following tranexamic acid in young patients carrying heterozygosity of MTHFR C677T

The objective of this study is to report a new manifestation of acute stroke following antifibrinolytic agent administration in young women carrying heterozygosity for methylene-tetrahydrofolate reductase (MTHFR) C677T. The study included two young women who developed an acute ischaemic stroke following three days of tranexamic acid administration for bleeding gynaecological disorders. Case 1, a 44-year-old woman, presented left hemiplegia, mild dysarthria and anosognosia. Brain magnetic resonance imaging showed right ischaemic fronto-temporal lesion due to subocclusion of the right middle cerebral artery. Case 2, a 49-year-old woman, developed aphasia and right hemiplegia. Neuroimaging showed left capsular and periventricular infarcts due to near occlusion of the left internal carotid artery. Thrombophilia screening, coagulation parameters, homocysteine testing, 12-lead electrocardiography, and transthoracic and transoesophageal echocardiography were unremarkable. Genetic assay showed that both patients carried heterozygosity for MTHFR C677T, in which cytosine (C) is replaced by thymidine (T) at base position 677. To our knowledge, this is the first report describing the association between genetic factors and the onset of stroke following antifibrinolytic drugs intake. These data suggest a synergic effect of plasminogen activator inhibitor and heterozygosity for MTHFR C677T on the pathogenetic mechanisms leading to ischaemic stroke in young people.

Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

To investigate effects of plasminogen activator inhibitor 1 (PAI-1) genetic deficiency and pharmacological PAI-1 inhibition with PAI-039 in a mouse model of radiation-induced enteropathy. Wild-type (Wt) and PAI-1(-/-) knockout mice received a single dose of 19 Gy to an exteriorized localized intestinal segment. Sham and irradiated Wt mice were treated orally with 1 mg/g of PAI-039. Histological modifications were quantified using a radiation injury score. Moreover, intestinal gene expression was monitored by real-time PCR. At 3 days after irradiation, PAI-039 abolished the radiation-induced increase in the plasma active form of PAI-1 and limited the radiation-induced gene expression of transforming growth factor beta1 (TGF-beta1), CTGF, PAI-1, and COL1A2. Moreover, PAI-039 conferred temporary protection against early lethality. PAI-039 treatment limited the radiation-induced increase of CTGF and PAI-1 at 2 weeks after irradiation but had no effect at 6 weeks. Radiation injuries were less severe in PAI-1(-/-) mice than in Wt mice, and despite the beneficial effect, 3 days after irradiation, PAI-039 had no effects on microscopic radiation injuries compared to untreated Wt mice. A genetic deficiency of PAI-1 is associated with amelioration of late radiation enteropathy. Pharmacological inhibition of PAI-1 by PAI-039 positively impacts the early, acute phase increase in plasma PAI-1 and the associated radiation-induced gene expression of inflammatory/extracellular matrix proteins. Since PAI-039 has been shown to inhibit the active form of PAI-1, as opposed to the complete loss of PAI-1 in the knockout animals, these data suggest that a PAI-1 inhibitor could be beneficial in treating radiation-induced tissue injury in acute settings where PAI-1 is elevated.

Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Glomerular microthrombosis (GMT) is not uncommon in lupus nephritis and has been associated with active renal injury and progressive kidney destruction. We undertook this study to determine whether genetic variations of hemostasis factors, such as plasminogen activator inhibitor 1 (PAI-1) and fibrinogen, affect the risk of GMT. A cross-sectional cohort of 101 lupus nephritis patients with or without GMT was genotyped for PAI-1 -675 4G/5G and beta-fibrinogen (FGB) -455 G/A gene polymorphisms and analyzed. PAI-1 4G/4G homozygotes and FGB A allele carriers were both at increased risk for GMT. When the data were stratified for both gene polymorphisms, an epistatic effect was detected. The PAI-1 4G/4G genotype was found to predispose to GMT not equally in all lupus nephritis patients, but only in FGB A allele carriers. Likewise, the association between the FGB A allele and GMT was restricted to lupus nephritis patients homozygous for the PAI-1 4G allele. This epistatic effect was revalidated by the multifactor dimensionality reduction (MDR) analysis and further assessed by incorporating a variety of environmental and clinical factors into the MDR analysis. The most parsimonious model that had a cross-validation consistency of 100% included joint effects of PAI-1 and FGB gene polymorphisms and anticardiolipin antibody (aCL) status and yielded the best prediction of GMT, with 66.6% accuracy. Our findings suggest that risk of GMT in lupus nephritis is attributable, at least in part, to an epistatic effect of PAI-1 and FGB genes, likely via an interaction with environmental/clinical factors, such as aCL.

Tissue-type plasminogen activator deficiency exacerbates cholestatic liver injury in mice

Recent studies demonstrating a role for plasminogen activator inhibitor (PAI)-1 in cholestatic liver disease in mice suggested that tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA) might be important after biliary tract obstruction. We now demonstrate that blocking tPA exacerbates liver injury after bile duct ligation (BDL). tPA deficient mice have increased bile infarcts, increased TUNEL positive cells, increased neutrophil infiltration, reduced hepatocyte proliferation and reduced ductular reaction 72 hours after BDL compared to wild type mice. In addition, the protective and proliferative effects of plasminogen activator inhibitor 1 (PAI-1) deficiency after BDL are dramatically blocked by the tPA inhibitor tPA-STOP. One potential mechanism for these effects is that both tPA deficiency and tPA-STOP reduce hepatocyte growth factor (HGF) activation and c-Met phosphorylation in the liver after BDL. In support of this hypothesis, HGF treatment reverses the effects of tPA deficiency in mice. Furthermore, preferential tPA activation in areas of injury after BDL might occur because fibrin accumulates in bile infarcts and activates tPA. tPA inactivation accelerates liver injury after BDL and reduces HGF activation. These data suggest that strategies to increase HGF activation might be protective in liver diseases with biliary tract obstruction even without increased HGF production.

Adipocytokines and incident diabetes mellitus in older adults: the independent effect of plasminogen activator inhibitor 1.

Adipose tissue produces "adipocytokines" of uncertain clinical significance. We analyzed the relationships among adiposity, adipocytokines, glycemia, and incident diabetes mellitus in 2356 white and black adults aged 70 to 79 years in the Health, Aging, and Body Composition Study who did not have diabetes at baseline. We measured the levels of adipocytokines adiponectin, leptin, interleukin 6, tumor necrosis factor alpha, and plasminogen activator inhibitor 1. Regional fat area was determined by means of computed tomography. New diabetes was defined as a self-reported diagnosis of diabetes or as a fasting plasma glucose level of 126 mg/dL or greater (>/=7.0 mmol/L) at the second, fourth, or sixth annual examination. A total of 143 participants (14.1 cases per 1000 person-years) developed diabetes across 5 years. Visceral fat area (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.10-1.60 per standard deviation increase) and body mass index (white individuals: OR, 1.65; 95% CI, 1.26-2.15 per standard deviation increase; black individuals: OR, 1.22; 95% CI, 0.99-1.51 per standard deviation increase) independently predicted incident diabetes. Adiponectin, leptin, and plasminogen activator inhibitor 1 attenuated the relationship between adiposity and diabetes. After controlling for body mass index, visceral fat, fasting glucose, fasting insulin, high-density lipoprotein cholesterol, triglycerides, and hypertension at baseline, plasminogen activator inhibitor 1 was the only adipocytokine independently associated with increased odds of diabetes (OR, 1.35; 95% CI, 1.01-1.81). Fasting glucose level at baseline remained a strong predictor of incident diabetes, whereas associations with body mass index and visceral fat were attenuated. Adipocytokines and glycemia partially account for the relationship between adiposity and risk of type 2 diabetes due to adiposity. Plasminogen activator inhibitor 1 may be a useful predictor of diabetes in addition to measurements of body fat.

Effect of plasminogen activator inhibitor–1 in diabetes mellitus and cardiovascular disease

Concentrations of plasminogen activator inhibitor–1 (PAI-1) are elevated beginning at the stage of impaired glucose tolerance and continuing through the development of diabetes mellitus and the metabolic syndrome. Evolving evidence of the central role of PAI-1 in mediating fibrosis and thrombosis increasingly supports the theory that it is a significant risk factor for macrovascular complications and cardiovascular disease, particularly in patients with diabetes. Several clinical studies have demonstrated a strong correlation between circulating PAI-1 levels and cardiovascular events and mortality. With the potentially severe effects of elevated PAI-1 levels becoming evident, there is increased interest in developing therapies targeted at reducing PAI-1 expression or circulating concentrations. Thus far, weight loss, inhibitors of the renin-angiotensin system, and insulin sensitization through use of thiazolidinediones (TZDs) appear to be the most promising strategies for managing elevated PAI-1 levels. Of these, TZD therapy is the only one that provides the benefits of both long-term glycemic control and improved cardiovascular risk profile. This article reviews the regulation of PAI-1, its activity in various disease states, and available treatment options.

The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent.

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1-/- aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin.

413 The effect of plasminogen activator inhibitor (PAI-1) released from washed platelets on the amidolytic activity of tissue-type plasminogen activator (t-PA)

413 The effect of plasminogen activator inhibitor (PAI-1) released from washed platelets on the amidolytic activity of tissue-type plasminogen activator (t-PA)