Elevated Plasma Plasminogen Activator Inhibitor-1 Research Articles

Plasminogen Activator Inhibitor-1 as a Marker of Thrombosis among Prehypertensive Patients: A Cross-sectional Study

Introduction: Impaired endogenous fibrinolysis has been shown to play a role in the pathogenesis and complications of hypertension. Plasminogen Activator Inhibitor-1 (PAI-1) is said to be a predictor of impaired fibrinolysis and thrombosis. Prehypertension is a common worldwide condition and is known to be an independent risk factor for Cardiovascular Disease (CVD). Aim: Present study aimed to measure plasma PAI-1 levels in prehypertensive patients and normal subjects and to find the correlation between elevated PAI-1 levels with Blood Pressure (BP), triglycerides, total cholesterol, Low-Density Lipoproteins (LDL) cholesterol, High-Density Lipoproteins (HDL) cholesterol, and urine albumin. Materials and Methods: This cross-sectional analytical study included 100 patients, comprising 50 prehypertensive individuals and 50 controls, aged between 35 and 50 years. The study was conducted at Sapthagiri Institute of Medical Sciences and Research Centre in Bangalore, India. Anthropometric measurements, PAI-1 levels, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and urine albumin were measured using standard procedures. The data were statistically analysed using the Statistical Package for Social Sciences (SPSS) version 10.0, applying Student t-test and Chisquare test. Correlation analysis was performed to assess the relationship between PAI-1 and various parameters. Results: A total of 100 patients were included in the study which had 64 men and 36 women with a mean age of 46±7 years. PAI-1 levels were significantly higher in the prehypertensive group compared to the control group (p-value=0.013). Participants with higher plasma PAI-1 levels had significantly elevated BP (p-value=0.001) compared to those with lower PAI-1 levels. Total cholesterol, triglycerides, and LDL cholesterol were significantly increased in prehypertensive individuals (p-value=0.001), whereas HDL cholesterol was significantly lower (p-value=0.001). The study also observed a significant increase in urine albumin in the prehypertensive group with elevated PAI-1 levels compared to the controls (p-value=0.001). The study revealed that elevated plasma PAI-1 levels did not show a significant positive correlation with SBP and DBP (r=0.138 and 0.660, p-value of 0.338 and 0.648, respectively). Plasma PAI-1 levels were weakly correlated with total cholesterol (r=0.145, p-value 0.315), LDL cholesterol (r=-0.068, p-value 0.640), HDL cholesterol (r=0.21, p-value 0.882), and triglycerides (r=0.207, p-value 0.150). There was no significant correlation between increased PAI-1 levels and urine albumin (r=-0.225, p-value of 0.117). Conclusion: Present study demonstrated that plasma PAI-1, total cholesterol, triglycerides, LDL cholesterol, and urine albumin were significantly elevated in prehypertensive individuals, suggesting vascular damage and inflammation. As prehypertension is often asymptomatic, patients with prehypertension should be considered to have an increased risk for CVD.

The role of the platelet pool of Plasminogen Activator Inhibitor-1 in well-controlled type 2 diabetes patients.

BackgroundThe main inhibitor of the fibrinolytic system, Plasminogen Activator Inhibitor -1 (PAI-1), irreversibly binds tissue-type Plasminogen Activator (t-PA) and thereby inhibits the protective action of tPA against thrombus formation. Elevated levels of plasma PAI-1 are associated with an increased risk of cardiovascular events and are observed in subjects with type 2 diabetes (T2D) and obesity. Platelets contain the majority of PAI-1 present in blood and exhibit the ability to synthesis active PAI-1. Diabetic platelets are known to be hyper-reactive and larger in size; however, whether these features affect their contribution to the elevated levels of plasma PAI-1 in T2D is not established.ObjectivesTo characterize the PAI-1 antigen content and the mRNA expression in platelets from T2D subjects compared to obese and lean control subjects, in order to elucidate the role of platelet PAI-1 in T2D.MethodsNine subjects with T2D and obesity were recruited from Primary Care Centers together with 15 healthy control subjects (8 lean subjects and 7 with obesity). PAI-1 antigen levels in plasma, serum and platelets were determined by ELISA, and PAI-1 mRNA expression was analyzed by qPCR.ResultsThere was no significant difference in PAI-1 mRNA expression or PAI-1 antigen in platelets in T2D subject in comparison to obese and lean control subjects. An elevated level of plasma PAI-1 was seen in both T2D and obese subjects. PAI-1 gene expression was significantly higher in both obese groups compared to lean.ConclusionSimilar levels of protein and mRNA expression of PAI-1 in platelets from T2D, obese and lean subjects indicate a limited role of platelets for the elevated plasma PAI-1 levels. However, an increased synthesis rate of mRNA transcripts in platelets from T2D and an increased release of PAI-1 could also result in similar mRNA and protein levels. Hence, synthesis and release rates of PAI-1 from platelets in T2D and obesity need to be investigated to further elucidate the role of platelets in obesity and T2D.

Increased expression of plasminogen activator inhibitor-1 (PAI-1) is associated with depression and depressive phenotype in C57Bl/6J mice.

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were found in depressed patients. Brain tissues from depressed individuals also showed stronger expression of hippocampal PAI-1 by confocal imaging in comparison to healthy individuals. Using a lipopolysaccharide-induced inflammatory model of depression in mice, we measured PAI-1 in murine plasma and brain, by ELISA and immunohistochemistry, respectively. Similar elevations were seen in plasma but not in brain homogenates of mice exposed to LPS. We further correlated the findings with depressive behavior. Ex vivo experiments with NHA treated with proinflammatory cytokines implicated in the pathogenesis of depression showed increased PAI-1 expression. Furthermore, these studies suggest that urokinase-type plasminogen activator may serve as an astrocyte PA reservoir, able to promote cleavage of brain-derived neurotrophic factor (BDNF) during stress or inflammation. In summary, our findings confirm that derangements of PAI-1 variably occur in the brain in association with the depressive phenotype. These derangements may impede the availability of active, mature (m)BDNF and thereby promote a depressive phenotype.

(870) - Elevated Plasma PAI-1 Levels in the Donor Are Associated with the Development of Primary Graft Dysfunction in Lung Transplant Recipients

Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality following lung transplantation. Early prediction of PGD would allow earlier interventions and better patient outcomes. Clinical factors, such as cigarette smoking, have been identified in the donor that increase the risk of PGD. Biological factors may also contribute. Elevated recipient plasma levels of plasminogen activator inhibitor-1 (PAI-1) and the receptor for advanced glycation end-products (RAGE) are known to be associated with a higher risk of developing PGD. However, these and other biomarkers in the donor plasma have not yet been shown to contribute to the risk of PGD. We tested the hypothesis that elevated donor plasma levels of PAI-1 and RAGE would be associated with recipient PGD. We carried out a prospective unmatched case control study for double lung transplants between June 2014 and September 2015. The primary outcome was donor plasma levels of PAI-1 and RAGE prior to organ recovery. We compared 12 recipients who developed PGD Grade 2 or 3 by ISHLT criteria within 72 hours postoperatively, with 13 recipients who did not. PaO2/FiO2 was measured concurrent with chest radiograph upon ICU arrival, 24, 48 and 72 hours postoperatively. Plasma biomarker levels in duplicate were compared between cases and controls using the Wilcoxon rank-sum test. Donor plasma levels of PAI-1 were significantly higher in those recipients who developed grade 2 or 3 PGD compared to those who did not (p=0.03) (Table). Plasma levels of PAI-1 remained significantly higher at 24 hours in the recipients that developed PGD compared to the non-PGD group (11.57 vs 1.95 ng/mL, p<0.001). RAGE was not statistically different between groups. Donor systemic inflammatory responses as reflected by significantly elevated plasma levels of PAI-1 may contribute to the risk of developing PGD. Rapid biomarker assessment may assist in donor lung selection and early risk stratification.Tabled 1Median donor plasma levels of PAI-1 and RAGE in cases versus controlsDonor Plasma BiomarkerCases (n=12) Median (IQR)Controls (n=13) Median (IQR)P valuePAI-1 (ng/mL)2.73 (2.07-5.51)1.39 (1.07-2.89)0.03RAGE (pg/mL)1061 (475 - 1930)679 (400-747)0.11IQR, interquartile range; PAI-1, plasminogen activator inhibitor-1; RAGE, receptor for advanced glycation end-products. Open table in a new tab

Abstract 606: Pharmacological Inhibition of PAI-1 Rescues Blood Flow Perfusion Through Promoting Capillary Arterialization in Diabetic Microangiopathy in Ischemic Limb

OBJECTIVE: Type II diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with DM. However, the role of PAI-1 in the development of DM-associated microvascular disease is poorly defined. RESEARCH DESIGN AND METHODS: Hind-limb ischemia was generated by femoral artery occlusion in diet-induced diabetic mice and age-matched normal chow (NC)-fed mice. Plasma was analyzed for glucose, non-esterified fatty acids, and PAI-1. PAI-039, a specific, small molecule pharmacological inhibitor of PAI-1, was orally administered to mice to determine if PAI-1 attenuates neovasculature formation in DM mice. RESULTS: PAI-1 activity and antigen were significantly increased within 2 weeks of DM onset and remained elevated throughout the experimental period. PAI-039 normalizes elevated plasma and ischemic muscles PAI-1 levels in the DM group. Pharmacologic inhibition of PAI-1 with PAI-039 rescued the ischemia-mediated impairments in blood flow perfusion and accelerated arterialization of capillaries in ischemic muscles in DM group compared to vehicle-DM group. Immunohistochemical analysis indicated increased expression of smooth muscle α-actin on capillary-sized vessels, and increased infiltration by CD45 leukocytes in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated mice. Furthermore, in these mice, VEGF-A was significantly down-regulated, and conversely, the expression of the PDGF-B and MMP 2, 9 were up-regulated in ischemic muscles in the inhibition of PAI-1 after induced ischemia. CONCLUSIONS: Taken together, these findings illustrate that the pharmacologic inhibition of elevated PAI-1 rescues the impairments in ischemia-mediated flow perfusion and capillary arterializations observed in DM, and may have efficacy as a therapeutic strategy to prevent diabetic microangiopathy.

Lipopolysaccharide-induced plasma PAI-1 increase does not correlate with PAI-1 synthesised de novo in the liver

Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue type plasminogen activator (t-PA) [ [1] Alessi M.C. Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol. 2006; 26: 2200-2207 Crossref PubMed Scopus (287) Google Scholar ]. High levels of plasma PAI-1 disrupt the fibrinolytic system to create a prothrombotic state that is associated with the development of pathological conditions such as thrombosis, fibrosis and cardiovascular diseases [ [1] Alessi M.C. Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol. 2006; 26: 2200-2207 Crossref PubMed Scopus (287) Google Scholar ]. Although the source of plasma PAI-1 under normal conditions and its increase in plasma under pathological conditions have been discussed, the source nevertheless remains obscure. Adipose tissue is generally considered the most likely contributor to elevated plasma PAI-1 under conditions of obesity [ [1] Alessi M.C. Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol. 2006; 26: 2200-2207 Crossref PubMed Scopus (287) Google Scholar ]. However, the liver is also an important contributor to the increase in plasma PAI-1 in obesity [ 2 Alessi M.C. Bastelica D. Mavri A. Morange P. Berthet B. Grino M. et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol. 2003; 23: 1262-1268 Crossref PubMed Scopus (153) Google Scholar , 3 Oishi K. Ohkura N. Wakabayashi M. Shirai H. Sato K. Matsuda J. et al. CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression. J Thromb Haemost. 2006; 4: 1774-1780 Crossref PubMed Scopus (79) Google Scholar , 4 Oishi K. Ohkura N. Matsuda J. Ishida N. Food deprivation induces adipose plasminogen activator inhibitor-1 (PAI-1) expression without accumulation of plasma PAI-1 in genetically obese and diabetic db/db mice. Thromb Haemost. 2007; 98: 864-870 PubMed Google Scholar ]. We have also shown that plasma PAI-1 levels are intricately associated with PAI-1 produced by the liver [ [5] Ohkura N. Shirakura M. Nakatani E. Oishi K. Atsumi G.-I. Associations between PAI-1 expression in various organs and its plasma concentrations in obese model mice. Thromb Res. 2012; 130: e301-e304 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ].

Association between Plasma Levels of Plasminogen Activator Inhibitor-1 and Colorectal Neoplasms

Background/AimsPlasminogen activator inhibitor-1 (PAI-1) is important for tumor growth, Invasion, and metastasis. In this study, we investigated the relationship between plasma levels of PAI-1 and colorectal adenomas.MethodsWe reviewed the medical records of 3,136 subjects who underwent colonoscopy as a screening exam. The subjects were classified into a case group with adenomas (n=990) and a control group (n=2,146). Plasma PAI-1 levels were categorized into three groups based on tertile.ResultsThe plasma levels of PAI-1 were significantly higher in adenoma cases than in controls (p=0.023). The prevalence of colorectal adenomas increased significantly with increasing levels of PAI-1 (p=0.038). In the adenoma group, advanced pathologic features, size, and number of adenomas did not differ among the three groups based on tertiles for plasma PAI-1 levels. Using multivariate analysis, we found that plasma level of PAI-1 was not associated with the risk of colorectal adenomas (p=0.675). Adjusted odds ratios for colorectal adenomas according to increasing plasma levels of PAI-1 were 0.980 (95% confidence interval [CI], 0.768 to 1.251) for the second-highest plasma level and 1.091 (95% CI, 0.898 to 1.326) for the highest level, compared with the lowest levels.ConclusionsThese results suggest that elevated plasma PAI-1 levels are not associated with the risk of colorectal neoplasms.

Abstract 52: Early Elevation of Plasma Plasminogen Activator Inhibitor-1 is Associated with Vasospasm following Subarachnoid Hemorrhage

Background: While the mechanism of early brain injury following subarachnoid hemorrhage (SAH) remains unclear, animal studies suggest that SAH is associated with significant changes in the fibrinolytic cascade. Human data shows that SAH-related brain ischemia is associated with the polymorphism in plasminogen activator inhibitor 1 (PAI-1) promotor linked to higher plasma PAI-1 levels. However, human plasma PAI-1 has not been previously studied in SAH. We hypothesize that elevated plasma PAI-1 is associated with VSP and poor outcome in SAH. Methods: In a prospective cohort of 61 SAH subjects, we compared plasma PAI-1 levels by ELISA (R&amp;D Systems) on post-SAH days 1, 5, 7 and 14 with respect to angiographic VSP and to functional outcome at 3- and 6-months. Angiographic VSP was defined as &gt;50% reduction in vessel caliber on post-SAH day 6-8 angiography. Poor functional outcome was defined as a modified Rankin score &gt;2. Biomarker levels were compared using Wilcoxon rank sum test. Bonferroni correction was applied for multiple comparisons. Results: Subjects with (n=25) and without VSP (n=36) were comparable in gender, Fisher and Hunt and Hess (HH) grade distribution, aneurysm treatment modality, and incidence of hydrocephalus. Subjects with VSP had lower mean age (50 vs. 56). Elevated plasma PAI-1 on post-SAH day 1 was strongly association with VSP (3.28 vs. 1.82 ng/mL; p=.0058) and showed a trend towards association with VSP on post-SAH day 5 (2.65 vs 1.83 ng/mL, p=0.05). Plasma PAI-1 levels were not associated with functional outcome at 3 or 6 months. Elevated plasma PAI-1 on post-SAH day 1 remained significantly associated with VSP (p=0.0155) after adjustment for age and HH and Fisher grades by logistic regression. Conclusion: Early elevation of plasma PAI-1 on post-SAH day 1 is strongly and independently associated with angiographic VSP in this small prospective SAH cohort and may be a candidate biomarker for VSP. Future mechanistic studies with simultaneous measurements of tissue plasminogen activator (tPA) and tPA-PAI complex and larger clinical studies are necessary to understand the utility of PAI-1 as potential biomarker in SAH.

Xanthoangelols isolated from Angelica keiskei inhibit inflammatory‐induced plasminogen activator inhibitor 1 (PAI‐1) production

The folk medicine Angelica keiskei (Ashitaba) exhibits antitumor, antioxidant and antidiabetic activities and it has recently attracted attention as a health food. Ashitaba is thought to have antithrombotic properties, but this has not yet been scientifically proven. The elevation of plasma plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis results in a predisposition to the risk of thrombosis. The present study showed that Ashitaba exudates injected intraperitoneally and orally administered over long-term suppressed the lipopolysaccharide (LPS) induced PAI-1 increase in mouse plasma. We also found that xanthoangelol, xanthoangelols B and D, the components of Ashitaba exudates, significantly inhibited TNFα-induced PAI-1 production from human umbilical vein endothelial cells (HUVECs). These findings suggest that Ashitaba can decrease elevated PAI-1 production, and that daily consumption of Ashitaba product might maintain anticoagulant status by inhibiting elevations in PAI-1 under inflammatory conditions.

Association of PAI-1 4G/5G and -844G/A Gene Polymorphisms and Changes in PAI-1/Tissue Plasminogen Activator Levels in Myocardial Infarction: A Case–Control Study

Myocardial infarction (MI) is induced by acquired and inherited risk factors, including the plasminogen activator inhibitor-1 (PAI-1) -844G/A and -675G/A (4G/5G) gene variants. The aim of this study was to investigate the association between PAI-1-844G/A and 4G/5G polymorphisms and changes in PAI-1 and tissue plasminogen activator (tPA) levels in MI in a Tunisian population. This was a case-control study involving 305 patients with MI and 328 unrelated healthy controls. PAI-1 genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (RFLP) (-844G/A) or by polymerase chain reaction-allele specific amplification. PAI-1 and tPA levels were assayed by serological assays. In contrast to tPA levels, mean plasma PAI-1 antigen levels were higher in cases than in control subjects. The elevation in PAI-1 levels was more pronounced in -844A and 4G allele carriers. Significantly higher frequencies of (mutant) 4G and -844A alleles and 4G/4G and -844A/-844A genotypes, and corresponding lower frequencies of (wild-type) 5G and -844G alleles and 5G/5G and -844G/-844G genotypes were seen in patients than in controls. Increased prevalence of 4G/-844A and decreased prevalence of 5G/-844G haplotypes were seen in patients than in controls, thereby conferring a susceptibility and protective nature to these haplotypes, respectively. Regression analysis confirmed the independent association of 4G/4G and -844A/A with MI, after controlling for a number of covariates. This study indicated that the risk of MI was notably high in 4G and -844A carriers with elevated plasma PAI-1 and were associated with reduced tPA levels.

Acute Ingestion of Long-Chain (n-3) Polyunsaturated Fatty Acids Decreases Fibrinolysis in Men with Metabolic Syndrome

Individuals with metabolic syndrome (MetS) often have elevated plasma plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA), contributing to an increased risk of cardiovascular disease. PAI-1 and t-PA may be affected by chronic (n-3) long-chain PUFA [(n-3)LCPUFA] supplementation; however, the acute impact of fat ingestion on these risk factors has not been established. Our objective was to investigate the acute effect of (n-3)LCPUFA on plasma PAI-1, t-PA, and platelet aggregation. We conducted a randomized crossover study in which men (n = 8, ≥45 y) with MetS consumed water or a high-saturated fat beverage (1 g fat/kg body weight) with either a high or low content of (n-3)LCPUFA. Blood samples were collected over 8 h to measure triacylglycerol (TAG), PAI-1, t-PA, and platelet aggregation. Both fat loads resulted in a significant increase in whole blood TAG concentration, plasma PAI-1 and t-PA concentrations, and PAI-1 activity, as well as a significant decrease in t-PA activity during the postprandial period. Interestingly, PAI-1 concentration and activity increased more following the high (n-3)LCPUFA compared with the low (n-3)LCPUFA beverage (P < 0.05). Furthermore, the high (n-3)LCPUFA beverage resulted in a lower t-PA activity (P < 0.05), whereas the effects of the 2 fat loads on the plasma t-PA concentration and platelet aggregation did not differ. Overall, acute intake of a high (n-3)LCPUFA beverage shifted the balance between plasma PAI-1 and t-PA, which might indicate a lower capacity for fibrinolysis.

A016 Association of PAI-1 4G/5G and -844G/A gene polymorphisms and changes in PAI-1/TPA levels in myocardial infarction. A casecontrol study

Myocardial Infarction (MI) was reportedly precipitated by acquired and inherited risk factors including the G/A and 4G/5G polymorphisms within the promoter of the Plasminogen Activator Inhibitor -1 (PAI-1) gene. to investigate the association between gene polymorphism of the PAI-1 and MI in Tunisian. PAI-1 G/A was genotyped with polymerase chain reaction — restriction fragment length polymorphism (PCR-RFLP) while PAI-1 4G/5G promoter genotype was established by allele specific polymerase chain reaction amplification of genomic DNA. This study was performed in 305 myocardial infarction patients and 328 unrelated healthy controls. All subjects clinical features and PAI-1 and t-PA activity were tested. There were two polymorphisms within the promoter (a G/A single base substitution polymorphism at -844 bp upstream from the start of transcription and an insertion (5G)/deletion (4G) polymorphism at position — 675). Higher frequency of the 4G allele (p < 0.001; O.R. = 1.929), but a lower frequency of the 5G allele (p < 0.001; O.R. = 0.356), were seen in patients vs. controls. The frequencies of the -844G (p < 0.001; O.R. = 0.314) allele was lower than -844A allele (p < 0.001; O.R. = 4.076) in patients versus controls. Furthermore significant elevation in plasma PAI-1 levels (88.43 ± 52.85 ng/ml vs. 62.18 ± 39.31 ng/ml; p <0.05) was seen among patients. This study indicates that the risk of MI was notably high in 4G carriers and A carriers with elevated plasma PAI-1, and were associated with reduced t-PA levels.

Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension

Elevated plasma plasminogen activator inhibitor-1 (PAI-1) is related to cardiovascular events, but its role in subclinical coronary microvascular dysfunction remains unknown. Thus, in the present study it was investigated whether elevated plasma PAI-1 activity is associated with coronary microvascular dysfunction in hypertensive patients. Thirty patients with untreated essential hypertension and 10 age-matched healthy controls were studied prospectively. Myocardial blood flow (MBF) was measured by using (15)O-water positron emission tomography. Clinical variables associated with atherosclerosis (low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, homeostasis model assessment (HOMA-IR), and PAI-1 activity) were assessed to determine their involvement in coronary microvascular dysfunction. Adenosine triphosphate (ATP)-induced hyperemic MBF and coronary flow reserve (CFR) were significantly lower in hypertensive patients than in healthy controls (ATP-induced MBF: 2.77+/-0.82 vs 3.49+/-0.71 ml x g(-1) x min(-1); p<0.02 and CFR: 2.95 +/-1.06 vs 4.25+/-0.69; p<0.001). By univariate analysis, CFR was positively correlated with HDL-cholesterol (r=0.46, p<0.02), and inversely with HOMA-IR (r=-0.39, p<0.05) and PAI-1 activity (r=-0.61, p<0.001). By multivariate analysis, elevated PAI-1 activity remained a significant independent determinant of diminished CFR. Elevated plasma PAI-1 activity was independently associated with coronary microvascular dysfunction, which suggests that plasma PAI-1 activity is an important clue linking hypofibrinolysis to the development of atherosclerosis.

Thrombin Activatable Fibrinolysis Inhibitor Antigen Levels Are Inversely Correlated with Plasminogen Activator Inhibitor-1 Antigen Levels in Hyperthyroid Patients

Both increased and decreased fibrinolytic activity have been reported in patients with hyperthyroidism. Elevated levels of plasma plasminogen activator inhibitor-1 (PAI-1) antigen have been found in hyperthyroid patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a novel plasma protein, which inhibits fibrinolysis through removal of C-terminal lysines from partially degraded fibrin. Previously, we showed that plasma TAFI antigen levels were increased in patients with overt and subclinical hypothyroidism. The aim of this study is to investigate plasma levels of TAFI and PAI-1 antigens in hyperthyroid patients. PAI-1 and TAFI antigen levels were measured in the plasma of 29 patients with hyperthyroidism (14 overt hyperthyroid and 15 subclinical hyperthyroid), and 26 healthy individuals. Although there were increased levels of PAI-1 antigen in hyperthyroid patients, plasma TAFI antigen levels were significantly lower compared to controls (80.79 ng/ml vs. 32.42 ng/ml, p = 0.000 for PAI-1; 10.42 microg/ml vs. 12.24 microg/ml, p = 0.009 for TAFI). Elevated PAI-1 antigen levels were positively correlated with free thyroid hormones, although TAFI antigen levels were in negative correlation with free thyroxine. Furthermore, an inverse correlation between PAI-1 and TAFI antigen levels was found. Our study demonstrated that TAFI antigen levels were decreased in patients with hyperthyroidism. Inverse correlation with PAI-1 suggests that the decrease in TAFI antigen levels may be due to activation of TAFI pathway. Further studies evaluating the underlying mechanisms of low TAFI antigen levels in hyperthyroidism should be undertaken.

Livedoid Vasculopathy Associated With Plasminogen Activator Inhibitor-1 Promoter Homozygosity (4G/4G) Treated Successfully With Tissue Plasminogen Activator

Livedoid vasculopathy (LV) is an occlusive thrombotic disease that affects primarily the small blood vessels of the lower extremities and often is associated with recurrent painful ulcerations. The pathogenesis of LV is unclear, but the disease is largely attributed to a hypercoagulable state. Factor V Leiden mutation, heterozygous protein C deficiency, homozygous hyperhomocysteinemia, and other inherited thrombophilias have been associated with LV. Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of the fibrinolytic system. Elevated levels of PAI-1 are found in some patients with thrombotic diseases. Some of these patients are homozygous for an allele of PAI-1 containing a stretch of 4 guanines at base -675 in the promoter region. This variant is associated with elevated PAI-1 protein levels, impaired fibrinolysis, and increased risk of thrombosis. A 33-year-old white woman had a 3-month history of painful enlarging ulcers on both ankles. Various therapies, including administration of oral antibiotic agents and prednisone up to 100 mg/d, to treat presumed vasculitis, were unsuccessful. Skin biopsy specimens revealed numerous thick-walled small blood vessels, many of which were filled with fibrin thrombi, in association with minimal perivascular inflammatory infiltrate, extensive epidermal necrosis, and focal ulceration. A diagnosis of thrombotic vasculopathy was made. Clinical workup revealed an elevated plasma level of PAI-1 (31 microM/mL; reference range, <25 microM/mL) and PAI-1 promoter 4G/4G homozygosity detected at DNA sequencing. Treatment with heparin sodium and tissue plasminogen activator dramatically improved the lesions, resulting in complete healing of the ulcerations. Continuation of anticoagulant therapy with warfarin sodium and episodic administration of tissue plasminogen activator was required for symptomatic control. Patients with LV may have elevated plasma PAI-1 levels. This may be associated with the PAI-1 promoter 4G/4G genotype, which has not previously been linked with LV. Further studies in patients with LV are warranted to determine how frequently this genotype is present because it may identify responsiveness to fibrinolytic therapy.

The determinants of plasma plasminogen activator inhibitor-1 levels differ for American and Japanese men aged 40–49

Background Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels. Methods We conducted a cross-sectional study on a total of 198 men aged 40–49 in the US (Body mass index (BMI): 27.0 ± 3.3 kg/m 2) and Japan (BMI: 23.3 ± 3.1 kg/m 2). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires. Results PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese. Conclusions PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40–49.

De novo synthesis of diacylglycerol in endothelium may mediate the association between PAI-1 and the insulin resistance syndrome

Increased free fatty acid flux, giving rise to increased de novo synthesis of diacylglycerol (DAG) and activation of protein kinase C (PKC) in vascular endothelium, may be largely responsible for the endotheliopathy and increased vascular risk associated with insulin resistance syndrome. This mechanism may also mediate, in large part, the increase in plasminogen activator inhibitor-1 (PAI-1) observed in this syndrome. PKC activation promotes transcription of PAI-1 in endothelial cells and other tissues, apparently by boosting the activity of Sp1 transcription factors that bind to the PAI-1 promoter. Plasma PAI-1 correlates inversely with the ability of insulin infusion to suppress free fatty acid levels. Moreover, infusion of triglycerides with heparin – inducing a marked increase in free fatty acids – has been shown to induce a rapid increase in plasma PAI-1. Alternatively, hyperinsulinemia and hypertriglyceridemia have been suggested as mediators of PAI-1 excess in insulin resistance, inasmuch as insulin and VLDL can stimulate PAI-1 production in cell cultures. However, plasma PAI-1 tends to decline in response to hyperinsulinemic clamps and insulin treatment of type 2 diabetes, and gemfibrozil treatment of hypertriglyceridemia does not decrease PAI-1 – suggesting that elevations of insulin or triglycerides are not likely to mediate PAI-1 excess in vivo. Hypertrophied adipose mass can secrete PAI-1, and is likely to contribute to the plasma PAI-1 pool in obese insulin-resistant subjects, but current evidence suggests that this is not likely to be the primary source of the elevated plasma PAI-1 in insulin resistance syndrome. Plasma PAI-1 can be decreased in insulin resistant subjects by improving adipocyte insulin sensitivity (with weight loss and thiazolidinediones), by consuming a very-low-fat diet that minimizes postprandial free fatty acid flux, and by administering activators of AMP-activated kinase (e.g., metformin), which can be expected to lessen tissue DAG synthesis.

Tumor Necrosis Factor α Activates the Human Plasminogen Activator Inhibitor-1 Gene through a Distal Nuclear Factor κB Site

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of plasminogen activation and likely plays important roles in coronary thrombosis and arteriosclerosis. Tumor necrosis factor-alpha (TNFalpha) is one of many recognized physiological regulators of PAI-1 expression and may contribute to elevated plasma PAI-1 levels in sepsis and obesity. Although TNFalpha is a potent inducer of PAI-1 expression in vitro and in vivo, the precise location of the TNFalpha response site in the PAI-1 promoter has yet to be determined. Transient transfection studies using luciferase reporter constructs containing PAI-1 promoter sequence up to 6.4 kb failed to detect a response to TNFalpha. Moreover, TNFalpha failed to induce expression of enhanced green fluorescent protein under the control of a 2.9-kb human PAI-1 promoter in transgenic mice, although endogenous murine PAI-1 was strongly induced. These data suggested that the TNFalpha response element in the PAI-1 gene is remote from the proximal promoter region. In this study, seven candidate regulatory regions were identified using cross-species sequence homology analysis as well as DNase I-hypersensitive site analysis. We identified a 5' distal TNFalpha-responsive enhancer of the PAI-1 gene located 15 kb upstream of the transcription start site containing a conserved NFkappaB-binding site that mediates the response to TNFalpha. This newly recognized site is fully capable of binding NFkappaB subunits p50 and p65, whereas overexpression of the NFkappaB inhibitor IkappaB prevents TNFalpha-induced activation of this enhancer element.

Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk

Elevated plasma plasminogen activator inhibitor-1 (PAI-1) level is a core feature of insulin-resistance syndrome (IRS). Atherothrombotic complications in IRS are partly attributed to impaired fibrinolysis caused by increased plasma PAI-1 levels. Although the etiology of IRS is far from being explained, the clustering of inflammation, adipose tissue accumulation and insulin resistance suggests an etiopathological link. Proinflammatory cytokines might regulate PAI-1 expression in IRS; however, more studies are needed to confirm this complex mechanism in humans. Furthermore, modifying PAI-1 expression by PAI-1 inhibitors provides a new challenge and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.

Plasminogen activator inhibitor-1 levels and polymorphisms.

To review the published evidence of a relationship between levels of plasminogen activator inhibitor-1 (PAI-1) or the 4G/5G polymorphism of the PAI-1 gene and the occurrence of venous thromboembolic disease. Review of the medical literature using computerized databases and a review of secondary sources identified through bibliographies. Plasminogen activator inhibitor-1 is an important inhibitor of the fibrinolytic system, so it is biologically plausible that elevated levels could suppress fibrinolysis and result in an increased risk of thrombosis. Several small studies reported associations between PAI-1 levels and venous thromboembolism, some of which appear to be familial. Problems with these studies include variations in PAI-1 plasma levels due to circadian changes and the acute phase response, as well as alterations due to common comorbid disease states. More recent investigations have focused on genetic polymorphisms, particularly the 4G/5G insertion/deletion in the promoter region, affecting transcription rates. The relation of 4G/5G to venous thrombosis has been investigated primarily in case-control studies, which have produced inconsistent findings. Most studies, however, have reported higher PAI-1 plasma levels in individuals with 4G/4G. The evidence regarding the relationship between an elevated PAI-1 plasma level or PAI-1 genetic polymorphism and the risk of venous thromboembolism is conflicting. There is insufficient information to recommend use of PAI-1 levels or genotype in evaluating thrombophilia.