Plasminogen Activator Inhibitor-1 Gene Research Articles

Residual vein thrombosis and onset of post-thrombotic syndrome: Influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene

Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity. Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n=85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n=83). All patients were treated according to current protocols and re-examined after 3, 12 and 36 months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36 months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment. These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis.

Plasminogen activator inhibitor-1 regulates LPS induced inflammation in rat macrophages through autophagy activation.

Background. The mechanisms by which plasminogen activator inhibitor-1 (PAI-1) regulates inflammation, especially in acute respiratory distress syndrome (ARDS), are largely unknown. Objective. To assess the relationship between PAI-1 and autophagy in inflammatory reactions induced by LPS in rat NR8383 cells. Methods. ELISA was used to assess the amounts of TNF-α, IL-1β, and PAI-1 in cell culture supernatants; TLR4, MyD88, PAI-1, LC3, Beclin1, and mTOR protein and mRNA levels were determined by western blot and quantitative RT-PCR, respectively; western blot was used to determine NF-κB protein levels. To further evaluate the role of PAI-1, the PAI-1 gene was downregulated and overexpressed using the siRNA transfection technology and the pCDH-PAI-1, respectively. Finally, the GFP Positive Expression Rate Method was used to determine the rate of GFP-LC3 positive NR8383 cells. Results. In LPS-induced NR8383 cells, TNF-α, IL-1β, and PAI-1 expression levels increased remarkably. Upon PAI-1 knockdown, TNF-α, IL-1β, PAI-1, TLR4, MyD88, NF-κB, LC3, and Beclin1 levels were decreased, while mTOR increased. Conversely, overexpression of PAI-1 resulted in increased amounts of TNF-α, IL-1β, PAI-1, TLR4, MyD88, NF-κB, LC3, and Beclin1. However, no significant change was observed in mTOR expression. Conclusions. In NR8383 cells, PAI-1 contributes in the regulation of LPS-induced inflammation, likely by promoting autophagy.

Alpha-lipoic acid inhibits peridural fibrosis following laminectomy through the inactivation of TGF-β1, PDGF, PAI-1 and IL-6 expressions.

The objective of this study was to investigate the antifibrotic effect of parenteral administration of alpha-lipoic acid (ALA), which has been reported to reduce fibrosis in the liver, oral mucosa, and peritoneum, in laminectomized rabbits as a potential candidate for the prevention of peridural fibrosis. Twelve adult New Zealand white male rabbits were divided into control (n=6) and ALA treatment groups (n=6). Laminectomy of the lumbar spine was performed in all animals, and ALA was administered intramuscularly in six rabbits composing the treatment group. Total RNA obtained from the paraffin-embedded tissues was analyzed for transforming growth factor-β1 (TGF-β1), plateletderived growth factor (PDGF), plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6). mRNA investigations showed that TGF-β1, PDGF, PAI-1 and IL-6 gene expressions, which constitute strong evidence for the development of fibrosis, were significantly lower in the treatment group compared with the results obtained from the control group. According to the histological peridural grading, the ALA-treated group showed significantly less peridural fibrosis than the control group. Intramuscular administration of ALA is a promising treatment for the prevention of peridural fibrosis in the postoperative period.

Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population.

BackgroundA keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk.Material/MethodsA total of 242 Chinese keloid patients and 207 controls were enrolled in this study. Polymerase chain reaction-restriction technique was used to determine PAI-1 promoter polymorphism (-675 4G/5G and -844 A/G) distribution. Plasma PAI-1 levels were detected using enzyme-linked immunosorbent assay (ELISA).ResultsThere was a statistically significant difference in the distribution of PAI-1 -675 4G/5G polymorphism between keloid patients and healthy controls. 4G/4G carriers were more likely to develop keloid. In contrast, the -844 A/G polymorphism distribution did not vary significantly between keloid patients and controls. The keloid patients group had a significantly higher plasma PAI-1 level than the control group. In the -675 4G/4G carrier population, the plasma PAI-1 levels were significant higher in keloid patients compared with controls.ConclusionsOur study provides evidence that PAI-1 promoter polymorphism -675 4G/5G and plasma PAI-1 level are associated with keloid risk. PAI-1 -675 4G/5G polymorphism may be an important hereditary factor responsible for keloid development in the Chinese Han population.

The drop that spilled the cup: acute myocardial infarction in a young woman with underlying thrombophilic polymorphisms and oral contraceptive use.

We present the case of a 28-year-old woman who was admitted to our cardiology unit for acute coronary syndrome. Her history was notable for cardiovascular disease familiarity, active smoking, and oral contraceptive use. On further analysis, she was noted to have thrombophilic polymorphisms involving the plasminogen activator inhibitor (PAI), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genes. We discuss the implications that these cofactors may have had in the genesis of the disease.

Identification of a Novel Compound That Suppresses Breast Cancer Invasiveness by Inhibiting Transforming Growth Factor-β Signaling via Estrogen Receptor α.

Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among females worldwide. An overwhelming majority of these deaths is because of metastasis. Estrogen stimulates and promotes growth of breast tumors, whereas transforming growth factor-beta (TGF-β) signaling promotes invasion and metastasis. We previously reported that estrogen and estrogen receptor alpha (ERα) suppressed breast cancer metastasis by inhibiting TGF-β signaling, whereas antiestrogens that suppress breast cancer growth, such as the selective ER modulator tamoxifen (TAM) or the pure antiestrogen fulvestrant (ICI 182,780), cannot suppress TGF-β signaling or breast cancer invasiveness. Therefore, we predicted that a compound that inhibits TGF-β signaling but does not facilitate ERα signaling would be ideal for suppressing breast cancer invasiveness and growth. In the present study, we identified an ideal candidate compound, N-23. Like estrogen, N-23 strongly decreased expression of TGF-β/Smad target gene plasminogen activator inhibitor-1 (PAI-1), but it did not increase the expression of ERα target gene pS2. While estrogen decreased the levels of phosphorylated Smad2 and Smad3, N-23 had no effect. In addition, TGF-β-dependent recruitment of Smad3 to the PAI-1 gene promoter was inhibited in the presence of estrogen or N-23. We also investigated the effects of N-23 on proliferation, migration, and invasion of breast cancer cells. In contrast to estrogen, N-23 inhibited the cellular proliferation of breast cancer cells. Moreover, we showed that N-23 suppressed the migration and invasion of breast cancer cells to the same extent as by estrogen. Taken together, our findings indicate that N-23 may be a candidate compound that is effective in inhibiting breast cancer progression.

Association of plasminogen activator inhibitor-1 gene polymorphism with inflammatory bowel disease in Iranian Azeri Turkish patients

Background/Aim:Previous studies have shown the association of some genetic factors, such as Plasminogen activator inhibitor type-1 (PAI-1) 4G/5G polymorphism, with the development of inflammatory bowel disease (IBD). We aimed to study this polymorphism as a risk factor in IBD patients in this cohort.Patients and Methods:One hundred and fifteen IBD patients and 95 healthy controls were selected from Iranian Azeri Turks and -6754G/5G polymorphism of PAI-1 gene was tested by polymerase chain reaction using allele-specific primers confirmed by sequencing.Results:There was no significant difference of PAI-1 polymorphism between IBD patients and the control group (P > 0.05). Furthermore, these data showed no significant difference between Crohn's disease and ulcerative colitis patients. However, 4G/4G homozygotes have reduced probability to progression of loss of appetite, whereas 5G/5G genotypes have increased risk for development of chronic diarrhea without blood, nausea, and loss of appetite.Conclusions:Although our study showed no significant association of PAI-1 polymorphism between patients and control group, the carriers of 4G/4G genotype and 4G allele had reduced risk for the progression of IBD features in this cohort.

4 G/4 G polymorphism of plasminogen activator inhibitor-1 gene increases the risk of diabetic nephropathy

Diabetic nephropathy (DN) has become the most common pathogenesis of end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of DN. A meta-analysis was conducted to investigate the association between 4 G/5 G variants in the PAI-1 gene and DN susceptibility. Databases including Pubmed, EMBASE, ISI, etc., were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. Ten studies involving 1366 cases and 1888 controls were included. Significant association between 4 G/4 G variant and DN risk was observed (OR 1.26, 95% CI 1.08–1.48, p = 0.004) in overall populations by the recessive model. 4 G allele was also associated with the risk of DN than the 5 G allele (OR 1.15, 95% CI 1.04–1.27, p = 0.008). In the subgroup analysis performed by the ethnicity, 4 G/4 G polymorphism was significantly associated with DN risk than 4 G/5 G + 5 G/5 G in East Asians (OR 1.42, 95% CI 1.03–1.96; p = 0.03), but not in Caucasians. In the stratified analysis by types of DM, the results showed significant association between 4 G/4 G variant and DN in Type-2 DM (OR 1.42, 95% CI 1.03–1.96, p = 0.03). In conclusion, 4 G/4 G phenotype of PAI-1 gene may be associated with DN risk. Additional larger studies should be conducted in future analyses.

Association of five common polymorphisms in the plasminogen activator inhibitor-1 gene with primary ovarian insufficiency

To investigate the association between potentially functional plasminogen activator inhibitor-1 (PAI-1) genetic polymorphisms and primary ovarian insufficiency (POI). Case-control study. Urban university-based hospital. A cohort of 137 POI patients and 227 controls. None. Genotyping of five PAI-1 polymorphisms (-844G>A [rs2227631], -675 4G/5G [rs1799889], 43G>A (Ala>Thr) [rs6092], 9785G>A [rs2227694], and 11053T>G [rs7242]) was assessed by polymerase chain reaction-restriction fragment length polymorphism assay. PAI-1 polymorphisms 9785GA+AA, -844A/9785A, 4G/9785A, and 9785A/11053G were associated with POI occurrence. Moreover, -844GA+AA and 11053TG+GG were associated with lower serum E2 levels in controls. We have identified an association between five PAI-1 polymorphisms and POI occurrence. However, the mechanism underlying the function of these polymorphisms in POI remains to be determined. Further studies are needed to improve understanding of the roles of PAI-1 polymorphisms and genes in related pathways, using a larger and more heterogeneous cohort.

Genetic polymorphisms in plasminogen activator inhibitor-1 predict susceptibility to steroid-induced osteonecrosis of the femoral head in Chinese population

BackgroundSteroid usage has been considered as a leading cause of non-traumatic osteonecrosis of the femoral head (ONFH), which is involved in hypo-fibrinolysis and blood supply interruption. Genetic polymorphisms in plasminogen activator inhibitor-1 (PAI-1) have been demonstrated to be associated with ONFH risk in several populations. However, this relationship has not been established in Chinese population. The aim of this study was to investigate the association of PAI-1 gene polymorphisms with steroid-induced ONFH in a large cohort of Chinese population.MethodsA case–control study was conducted, which included 94 and 106 unrelated patients after steroid administration recruited from 14 provinces in China, respectively. Two SNPs (rs11178 and rs2227631) within PAI-1 were genotyped using Sequenom MassARRAY system.Resultsrs2227631 SNP was significantly associated with steroid-induced ONFH group in codominant (P = 0.04) and recessive (P = 0.02) models. However, there were no differences found in genotype frequencies of rs11178 SNP between controls and patients with steroid-induced ONFH (all P > 0.05).ConclusionsOur data offer the convincing evidence for the first time that rs2227631 SNP of PAI-1 may be associated with the risk of steroid-induced ONFH, suggesting that the genetic variations of this gene may play an important role in the disease development.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1569909986109783.

Patients who have 4G Alleles in Plasminogen Activator Inhibitor1 Gene Have Higher Mean Platelet Volume Values at the Time of ST-Elevation Myocardial Infarction

Patients who have 4G Alleles in Plasminogen Activator Inhibitor1 Gene Have Higher Mean Platelet Volume Values at the Time of ST-Elevation Myocardial Infarction

The Role of (-675G/A) 4G/5G Polymorphism of the Plasminogen Activator Inhibitor-1 Gene on Atrial Fibrillation with Ischemic Stroke in Turkish Population

PP-103 Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis, and the common promoter region variants -675G/A (4G/5G) is associated with increased thrombotic risk. High levels of PAI-1 have been implicated as a risk factor for cardiovascular disease. The 4G allele is associated with

Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children

ObjectiveTo assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. MethodsA cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. ResultsThe prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (b = 0.02, p = 0.006), waist circumference (b = 4.42, p = 0.009), and subscapular skinfold thickness (b = 1.79, p = 0.04); however, it was not related with insulin resistance. ConclusionThe -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.

Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor

BackgroundAdvanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear.MethodsIn this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs.ResultsDPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10-5 M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs.ConclusionsThe present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes.

GW24-e3717 Relationship between PAI-1 promotor region gene 4G/5G polymorphism and pulmonary thromboembolism

ObjectivesTo investigate the relationship between plasminogen activator inhibitor-1(PAI-1) promotor region gene 4G/5G polymorphism and pulmonary thromboembolism (PTE) and detect whether it plays an important role in the pathogenesis of pulmonary...

Correlation between plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G polymorphism and metabolic/proinflammatory factors in polycystic ovary syndrome

Polycystic Ovary Syndrome (PCOS) is the most common cause of subfertility associated to metabolic disorders. The aim of this study was to correlate metabolic and proinflammatory factors in women with PCOS. The frequency of Plasminogen Activator Inhibitor-1 (PAI-1) promoter 4 G/5 G polymorphism was also compared to healthy controls. We evaluated 79 PCOS and 79 healthy women. PAI-1 levels are positively correlated with proinflammatory factors in PCOS group. 4 G allele in PAI-1 gene was more frequent in PCOS and the 4G/4 G genotype was associated with increased PAI-1 levels. A correlation between insulin resistance and proinflammatory and overweight was also observed. C-reactive protein, serum levels of vascular cell adhesion molecule-1 (sVCAM-1), Lipid Accumulation Product (LAP) and vitamin D are good tools to evaluated factors associated to cardiovascular risk in women with PCOS.

Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children

ObjectiveTo assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. MethodsA cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, state of Guerrero, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. ResultsThe prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β=0.02, p=0.006), waist circumference (β=4.42, p=0.009), and subscapular skinfold thickness (β=1.79, p=0.04); however, it was not related with insulin resistance. ConclusionThe -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.

Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species

While transforming growth factor-β (TGF-β1)-induced SMAD2/3 signaling is a critical event in the progression of chronic kidney disease, the role of non-SMAD mechanisms in the orchestration of fibrotic gene changes remains largely unexplored. TGF-β1/SMAD3 pathway activation in renal fibrosis (induced by ureteral ligation) correlated with epidermal growth factor receptorY845 (EGFRY845) and p53Ser15 phosphorylation and induction of disease causative target genes plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) prompting an investigation of the mechanistic involvement of EGFR and tumor suppressor p53 in profibrotic signaling. TGF-β1, PAI-1, CTGF, p53 and EGFR were co-expressed in the obstructed kidney localizing predominantly to the tubular and interstitial compartments. Indeed, TGF-β1 activated EGFR and p53 as well as SMAD2/3. Genetic deficiency of either EGFR or p53 or functional blockade with AG1478 or Pifithrin-α, respectively, effectively inhibited PAI-1and CTGF induction and morphological transformation of renal fibroblasts as did SMAD3 knockdown or pretreatment with the SMAD3 inhibitor SIS3. Reactive oxygen species (ROS)-dependent mechanisms initiated by TGF-β1 were critical for EGFRY845 and p53Ser15 phosphorylation and target gene expression. The p22Phox subunit of NADPH oxidase was also elevated in the fibrotic kidney with an expression pattern similar to p53 and EGFR. EGF stimulation alone initiated, albeit delayed, c-terminal SMAD3 phosphorylation (that required the TGF-β1 receptor) and rapid ERK2 activation both of which are necessary for PAI-1 and CTGF induction in renal fibroblasts. These data highlight the extensive cross-talk among SMAD2/3, EGFR and p53 pathways essential for expression of TGF-β1-induced fibrotic target genes.

Association between PAI-1 4G/5G Polymorphisms and osteonecrosis of femoral head: A Meta-analysis

The polymorphism of the plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G gene has been correlated with susceptibility to osteonecrosis of the femoral head (ONFH), but study results are controversial. The aim of this study was to derive a more precise estimation of the relationship between the PAI-1 4 G/5 G Gene polymorphism and ONFH by performing a meta-analysis. The meta-analysis was based on five eligible case-control studies involving 419 cases and 969 controls and summarized data indicating the association between PAI-1 polymorphism and risk of osteonecrosis of the femoral head. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to assess the strength of this association in the random-effects model or fixed-effects model. A significant association between PAI-1 4 G/5 G polymorphism and ONFH susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR=1.766, 95% CI 1.279-2.437, P=0.001), 4 G/4G vs. 4 G/5 G+5G/5 G (OR=2.050, 95% CI 1.581-2.657, P=0.000), 4 G/4G vs. 5 G/5G (OR=2.553, 95% CI 1.345-4.846, P=0.004), and 4 G vs. 5 G (OR=1.758, 95% CI 1.236-2.500, P=0.002). No significant association between PAI-1 4 G/5 G polymorphism and ONFH susceptibility was observed for 4 G/5 G vs. 5 G/5G (OR=1.327, 95% CI 0.939-1.877, P=0.109). This meta-analysis suggested that 4 G/5 G polymorphism of the PAI-1 gene was a risk factor for ONFH. This study also suggests that the PAI-1 4G4G genotype may indicate a risk for ONFH.

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 ].