Higher Plasminogen Activator Inhibitor Type 1 Levels Research Articles

PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age.

Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our prior work demonstrated that PAI-1 in plasma is positively associated with acute kidney injury (AKI) in septic patients and mice. The objective of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis. Sepsis was induced by cecal slurry (CS)-injection to wild-type (WT, C57BL/6) and PAI-1 knockout (KO) mice at young (5-9months) and old (18-22months) age. Survival was monitored for at least 10 days or mice were euthanized for tissue collection at 24 or 48h post-insult. Contrary to our expectation, PAI-1 KO mice at old age were significantly more sensitive to CS-induced sepsis compared to WT mice (24% vs. 65% survival, p = 0.0037). In comparison, loss of PAI-1 at young age had negligible effects on sepsis survival (86% vs. 88% survival, p = 0.8106) highlighting the importance of age as a biological variable. Injury to the kidney was the most apparent pathological consequence and occurred earlier in aged PAI-1 KO mice. Coagulation markers were unaffected by loss of PAI-1, suggesting thrombosis-independent mechanisms for PAI-1-mediated protection. In summary, although high PAI-1 levels are clinically associated with worse sepsis outcomes, loss of PAI-1 rendered mice more susceptible to kidney injury and death in a CS-induced model of sepsis using aged mice. These results implicate PAI-1 as a critical factor in the resolution of sepsis in old age.

Polymorphism of the plasminogen activator inhibitor type 1 gene, plasminogen level and thrombosis in patients with antiphospholipid syndrome

The frequency of venous and arterial thromboses and plasminogen level were investigated in 78 patients with antiphospholipid syndrome (APS), 35 of whom with systemic lupus erythematosus (SLE+APS) and 43 - with primary APS (PAPS). The levels and genotype of plasminogen activator inhibitor type 1 (PAI-1) were determined in 45 patients with APS, of whom 21 patients with SLE + APS and 24 patients with PAPS. A control group included 10 healthy individuals without autoimmune disease signs and thromboses on period of investigation and in past history. It was shown for the first time that for one third of 67 patients with APS and thromboses high positive levels of antiphospholipid antibodies (aPL) are associated with low plasminogen levels. The levels of PAI-1 antigen measured by ELIZA method, which detects active, latent and bound with plasminogen activator PAI-1, were opposed with frequency of thromboses in APS patients. Correlation between the high and increased levels of PAI-1 and high positive aPL levels was found for one third of 43 patients with APS and thrombosis. One of the possible mechanisms of this interconnection was considered. It was shown that arterial and, to a more extent, venous thromboses are associated with the 4G/5G polymorphism of PAI-1 gene and high plasma level of the inhibitor in 79% of APS patients. At the presence of the 4G allele patients with SLE+APS had higher PAI-1 levels than patients with PAPS. The obtained results show that measuring the levels of plasminogen and PAI-1 as well as the 4G/5G polymorphism of PAI-1 gene which is associated with thromboses may have the practical significance for identification of high risk of thrombosis in APS patients.

4G/5G polymorphism modulates PAI-1 circulating levels in obese women

The increase in plasminogen activator inhibitor type 1 (PAI-1) has been described as a risk factor to thrombosis-related diseases. In addition, it has been demonstrated that the variant 4G of polymorphism 4G/5G located in promoter region of PAI-1 gene is associated with higher PAI-1 levels. We investigate the role of this polymorphism on circulating PAI-1 concentration in a population of 57 obese women (23%, 4G/4G; 49%, 4G/5G and 28%, 5G/5G genotypes). Our results demonstrate a genotype-specific modulation on PAI-1 levels in obese women, thus 5G/5G genotype presented significantly lower levels of plasma PAI-1 when compared to 4G/4G group (46 ± 19 ng/mL vs. 63 ± 13 ng/mL, respectively). Our findings indicate that obese carriers of 4G/4G genotype may have increased risk to develop thrombotic diseases.

Plasminogen activator inhibitor type 1 (PAI-1) is a valuable biomarker for predicting the metabolic syndrome (MS) in institutionalized elderly residents in Taiwan

Circulating levels of inflammatory and prothrombotic factors are elevated in the metabolic syndrome (MS) and linked with the occurrence of cardiovascular events. The aim of our study was to investigate the relationship between inflammatory and prothrombotic markers and the MS in elderly institutionalized residents. A total of 326 non-diabetic residents of Chuang-Hua Veterans Care Home (age: 79.9±4.1 years; 100% males) were enrolled. MS was diagnosed according to the AHA/NHLBI Scientific Statement criteria. Body fat percentage was measured by bioelectrical impedance analysis. Insulin resistance was calculated by homeostasis model assessment for insulin resistance (HOMA-IR). Inflammatory markers, including tumor necrosis factor-a (TNF-α), high sensitivity C-reactive protein (hsCRP), and plasminogen activator inhibitor-1 (PAI-1), were determined using ELISA. Elderly residents with the MS had higher systolic and diastolic blood pressures (both p < 0.001) and higher HOMA-IR (p < 0.001), hsCRP (p = 0.008), and PAI-1 levels (p < 0.001) than those without the MS. On multivariate logistic regression analysis, PAI-1 was an independent risk factor for the MS. Of the MS components, elderly residents with higher waist circumferences and higher levels of plasma fasting glucose, and triglyceride (TG), and lower levels of high density lipoprotein (HDL) had higher PAI-1 levels than those without the above components.

Plasminogen activator inhibitor type 1 gene polymorphisms and haplotypes are associated with plasma plasminogen activator inhibitor type 1 levels but not with myocardial infarction or stroke

The 4G allele in the promoter region of the plasminogen activator inhibitor type 1 (PAI-1) gene is associated with higher plasma PAI-1 levels and activity, but its association with cardiovascular diseases is unclear. We investigated the association of polymorphisms and common haplotypes of the PAI-1 gene with plasma PAI-1 levels, as well as the risk of myocardial infarction and stroke. This study is a prospective analysis of 2995 community-based participants (41% blacks and 51% women) aged 70 to 79 years old in the Health, Aging, and Body Composition Study. From 1997/1998 to 2001, 177 myocardial infarction events and 101 stroke events were identified. In addition to the 4G/5G polymorphism, 2 potential functional variants and other 4 haplotype-tagging variants were genotyped. In general linear models, the 4G allele was associated with higher PAI-1 levels after adjusting for age, sex, race, and site (26, 29, and 32 ng/mL for 5G/5G, 4G/5G, and 4G/4G, respectively; P for trend < .0001), but none of the other 6 polymorphisms was associated with PAI-1 levels. Haplotype analysis produced similar results. However, in Cox proportional hazard models, neither the polymorphisms nor the common haplotypes of the PAI-1 gene was associated with the risk of either myocardial infarction or stroke. The 4G allele is associated with higher PAI-1 levels, but this study does not support an association of the PAI gene polymorphisms with the risk of either myocardial infarction or stroke.

Fibrinolytic dysfunction in insulin‐resistant women with previous gestational diabetes

Women with a history of gestational diabetes (p-GDM) are at increased risk of developing type 2 diabetes mellitus (DM2) later in life, and therefore at increased risk for future cardiovascular disease. Three months after delivery we investigated the plasma levels of plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen and von Willebrand factor (vWF) in 74 women with p-GDM and 20 healthy females with normal glucose tolerance during and after pregnancy, as well as the relation of fibrinolytic parameters to insulin resistance and glycaemic control. All women underwent an oral (OGTT) as well as an intravenous glucose tolerance test (FSIGT). Mathematical model analysis disclosed that 50% (n=37 each) of the p-GDM subjects had normal (NIS) or impaired (IIS) insulin sensitivity. Parameters of interest were determined using commercially available test systems. Women with p-GDM and IIS had significantly increased body fat mass (BFM) (P<or=0.001) compared with women with p-GDM and NIS and controls, whereas the waist to hip ratio (WHR) was similar in both p-GDM groups but was higher compared with the controls (P<or=0.001). Mean PAI-1 and t-PA as well as fasting and stimulated plasma concentrations of proinsulin, C-peptide and insulin were elevated, whereas the disposition index was lower in women with p-GDM and IIS compared with women with p-GDM and NIS and the controls (P<0.001). Plasma levels of fibrinogen and vWF did not differ between the groups. Obese women with IIS had higher PAI-1 levels than lean women with IIS (P<or=0.001). PAI-1 inversely correlated with the insulin sensitivity index (SI) but only in women with IIS (P<0.0001). On regression analysis, only fasting proinsulin and WHR remained significant independent predictors of PAI-1 elevation in IIS (P<or=0.0001 and P<or=0.001). The PAI-1/SI ratio was elevated in women with IIS independently of their glucose tolerance status (P<0.001 vs. NIS and controls). Plasminogen activator inhibitor type 1 is elevated in p-GDM women with IIS and depends on plasma proinsulin and abdominal obesity. An increase of the PAI-1/SI ratio further characterizes obese insulin-resistant p-GDM women who may be at risk for diabetes and angiopathy.

Androgens Are Associated with Hemostatic and Inflammatory Factors among Women at the Mid-Life

The goal of this study was to relate annually measured endogenous androgens to hemostatic and inflammation markers in women longitudinally. A total of 3302 participants from the Study of Women's Health Across the Nation, aged 42-52 yr at baseline and self-identified as African-American (28%), Caucasian (47%), Chinese (8%), Hispanic (8%), or Japanese (9%) were evaluated for testosterone (T), dehydroepiandrosterone sulfate, and SHBG at four time points in 5 yr. Cardiovascular disease markers were fibrinogen, activated factor VII-c, C-reactive protein (hsC-RP), and the fibrolytic factors, plasminogen activator inhibitor type 1 (PAI-1), and tissue plasminogen activator [t(PA)]. T and free androgen index (FAI) were associated highly positively with PAI-1 and t(PA), and FAI was associated highly and positively with hsC-RP. Lower SHBG levels, associated with greater bioavailable T, were associated significantly with higher levels of PAI-1, t(PA), hsC-RP, and factor VII-c. SHBG was lower in Chinese and Japanese women markedly, resulting in FAI values that, on average, were higher among Chinese and Japanese women compared with African-American, Caucasian, and Hispanic women. There were strong, positive associations of androgens with fibrolytic and inflammation markers, even after considering age, body size, smoking, and race/ethnicity. It is important to study androgens, their precursors, and their carrier protein as part of the risk profile for heart disease in mid-aged women.

The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke

High levels of plasminogen activator inhibitor type 1 (PAI-1) have been implicated as a risk factor for cardiovascular disease, but its precise role remains controversial. The 4G allele of the PAI-1 4G/5G promoter polymorphism is associated with higher levels of PAI-1. We studied the relationship between ischemic stroke and the PAI-1 4G/5G polymorphism and PAI-1 antigen levels. We performed a case-control study among patients aged 18-75 years with first ischemic stroke, confirmed by CT. All patients were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. We excluded patients with a definite non-atherosclerotic cause of the stroke and patients using oral anticoagulants. Population-controls were age -and sex-matched, without a history of stroke, and of the Caucasian race. Venous blood samples were taken for PAI-1 4G/5G polymorphism and PAI-1 level one week after stroke. We included 124 patients and 125 controls. Mean age was 56 yrs (range 18 to 75 yrs). Sixty one patients (50%) and 58 (47%) controls were heterozygous for the PAI-1 4G/5G polymorphism. The homozygous 4G/4G genotype was found in 33 patients (27%) and in 36 controls (29%). The odds ratio of ischemic stroke associated with 4G-carriers versus 5G/5G homozygotes was 1.0 (95% CI: 0.6-1.8). The relative risk of ischemic stroke associated with the level of PAI-1 in the upper quartile was 0.73 (95%CI: 0.4 to 1.4). Neither the PAI-1 4G/5G polymorphism nor the PAI-1 antigen level is a strong risk factor for ischemic stroke.

PAI-1 and EGFR expression in adult glioma tumors: toward a molecular prognostic classification

Purpose : Molecular classification of gliomas is a major challenge in the effort to improve therapeutic decisions. The plasminogen activator system, including plasminogen activator inhibitor type 1 (PAI-1), plays a key role in tumor invasion and neoangiogenesis. Epidermal growth factor receptor (EGFR) is involved in the control of proliferation. The contribution of PAI-1 and EGFR to the survival of gliomas was retrospectively investigated. Methods and Materials : Fifty-nine adult gliomas treated by neurosurgery and conventional irradiation were analyzed, including 9 low-grade (2) and 50 high-grade (3–4) tumors (WHO classification). PAI-1 was measured on cytosols and EGFR on solubilized membranes using ELISA methods. Results : High PAI-1 levels were strongly associated with high histologic grade ( p < 0.001) and histologic necrosis ( p < 0.001). PAI-1 also correlated positively with patient age ( p = 0.05) and negatively with Karnofsky index ( p = 0.01). By univariate analysis of the high-grade population, higher PAI-1 ( p < 0.0001) and EGFR values ( p = 0.02) were associated with shorter overall survival. Only PAI-1 was an independent factor in multivariate analysis. Grade 3 tumors with low PAI-1 (100% 3-year overall survival rate) presented the same clinical outcome as the low-grade tumors. Conclusions : In this prognostic study, PAI-1 and EGFR expression revealed similarities and differences between high-grade gliomas that were not apparent by traditional clinical criteria. These data strongly support that biologic factors should be included in glioma classification and the design of clinical trials to treat more homogeneous populations.

Plasminogen activator inhibitor type 1 in ischemic cardiomyopathy.

Plasminogen activator inhibitor type 1 (PAI-1) is a proteinase inhibitor1 constituting the key regulator2 of the activity of the fibrinolytic system, an important protective mechanism against thrombosis. Because a reduced fibrinolytic activity, mainly caused by increased plasma levels of PAI-1, was a common finding in cross-sectional studies of patients with coronary artery disease (CAD),3 high PAI-1 levels have been regarded as a risk factor for recurrent myocardial infarction (MI).4 5 6 It has also been proposed that a reduced fibrinolytic activity may have a role in atherosclerotic plaque formation and in a prothrombotic state, carrying an increased risk of arterial occlusion. Accordingly, over the last few years, several studies have been performed to investigate the role of plasma PAI-1 levels in the development of CAD and MI. Moreover, the observation that polymorphisms of the PAI-1 gene exist, some of which apparently associated with increased plasma PAI-1 levels, stimulated studies aiming at investigating the potential relation between PAI-1 genotypes and ischemic cardiomyopathy. Thus, we shall focus on recent advances in the knowledge of the role of PAI-1 and its gene in the development of ischemic cardiomyopathy. Intravascular fibrinolytic activity results from a balance between plasminogen activators, such as the tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and inhibitors, such as PAI-1 and α2-antiplasmin. PAI-1 is a glycoprotein with a molecular mass of ≈54 kDa that belongs to the serine protease inhibitor superfamily (serpins). Its primary structure was deduced from the sequence of its cDNA.7 It is considered the major physiological inhibitor of t-PA and urokinase, because plasmin formation and fibrinolysis, as well as formation of other extracellular proteases, strongly depend on PAI-1 levels.8 Although the principal source of plasma PAI-1 is unknown, available evidence indicates that several cell types, including endothelial and vascular …

Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from node-positive breast cancer patients.

Cancer cell invasion is accomplished by the concerted action of several extracellular proteolytic enzyme systems, one of which is the urokinase plasminogen activation system. The different components of this system. e.g. urokinase plasminogen activator (uPA), its receptor uPAR, as well as its main inhibitor plasminogen activator inhibitor type 1 (PAI-1) have all been shown to have prognostic value in breast cancer, i.e. high tumor levels are associated with a poor prognosis. In order to further substantiate the prognostic value of uPA and PAI-1, we have tested the cutpoints (median values and optimized outpoints) from our first study (Cancer Res 53: 2513-2521, 1993) in an independent group of breast cancer patients. Breast cancer cytosols from 100 premenopausal and 150 post-menopausal node positive patients were included. The median observation time was 80 months (range 49-145). Univariate analysis showed that high PAI-1 levels (above the median PAI-1 value) were significantly associated with short recurrence-free survival (RR: 1.65; 95% CI: 1.04-2.63; P = 0.03) and short overall survival (RR: 2.46; 95% CI: 1.52-3.96; P = 0.0001) in postmenopausal patients. Postmenopausal patients with high uPA levels (above the median uPA value) had a significantly shorter recurrence-free survival (RR: 2.04; 95% CI: 1.17-3.56; P = 0.01) and overall survival (RR: 2.07; 95% CI: 1.16-3.70; P = 0.01) than patients with low uPA values. Nearly identical results were obtained when using the optimized PAI-1 or uPA value. In a Cox multivariate analysis which included other established prognostic factors, high PAI-1 was found to be an independent prognostic variable predicting short overall survival with a relative risk of 2.27 in postmenopausal women, and high uPA was found to be an independent prognostic variable predicting short recurrence-free survival with a relative risk of 1.86 in postmenopausal women. The present study indicates that uPA and PAI-1 are independent and significant prognostic variables in subsets of breast cancer patients.

Recombinant plasminogen activator inhibitor type 1

Plasminogen activator inhibitor type 1 (PAI-1), a member of the serpin family of serine protease inhibitors, inhibits both tissue-type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA). High PAI-1 levels are associated with an increased risk of thromboembolic disease while PAI-1 deficiency may represent an inherited autosomal recessive bleeding disorder. This review describes the biochemistry of PAI-1 including its purification, conversion between active and latent forms, and interaction with its target serine proteases and its protein cofactor, vitronectin. In addition, an overview of animal studies with PAI-1 is presented to examine its role in regulating fibrinolysis in vivo. For this review, particular emphasis is placed on studies with a recombinant form of bacterially expressed PAI-1 (rPAI-1), which shares many features in common with the active form of native PAI-1.

Role of plasminogen activator inhibitor type 1 in the pathogenesis of coronary artery diseases.

Patients with ischaemic heart disease have high levels of plasminogen activator inhibitor type 1 (PAI-1). These levels can constitute an independent thrombotic risk factor. In addition, PAI-1 synthesis is greater in the atherosclerotic vessels than in the normal vessels and this can also constitute an atherogenic risk factor. There is a good correlation between insulinaemia and PAI-1, but it has not been demonstrated that the circulating level of PAI-1 depends exclusively on insulinaemia. The increased levels of PAI-1 correlate with other coronary risk factors, especially hypertriglyceridaemia, but high PAI-1 levels are also found in normolipaemic patients. Vascular synthesis of PAI-1 can be promoted by high levels of circulating lipoprotein a. Finally, an exercise programme can increase the fibrinolytic activity of heart disease patients towards normal.

Normal plasminogen activator inhibitor levels at long-term follow-up after jejuno-ileal bypass surgery in morbidly obese individuals

Forty-five patients who had been subjected to jejuno-ileal bypass (JIB) surgery for morbid obesity and 10 obese nonsurgery subjects were studied. The former group was examined 14 to 20 years ffter surgery, and was found to have lower mean plasminogen activator inhibitor type 1 (PAI-1) activity (8.4 v 32 U/mL, P < .001), tissue plasminogen activator (tPA) antigen concentrations (7.2 v 12 μg/L, P < .01), body mass index (BMI), and fasting plasma insulin, triglyceride, and cholesterol levels. The PAI-1 levels were correlated with BMI, waist to hip ratio, and insulin, triglyceride, and cholesterol levels. Thus, previously obese subjects have normal PAI levels 14 to 20 years after treatment with JIB surgery, in contrast to the high PAI-1 levels in nonsurgery obese subjects.