Association Of Plasminogen Activator Inhibitor-1 Research Articles

Thrombotic risk assessed by PAI-1 in patients with COVID-19: The influence of hyperglycemia and diabetes mellitus

ObjectiveTo assess thrombotic risk with PAI-1 levels in patients with COVID-19, to evaluate PAI-1 differences between hyperglycemic and/or Type 2 Diabetes Mellitus (T2DM) versus non-hyperglycemic patients, and to analyze the association of plasminogen activator inhibitor-1 (PAI-1) with hyperglycemia and T2DM. MethodsA cross-sectional study carried out in 181 patients hospitalized for COVID-19. Two groups were formed: the patients with hyperglycemia at admission and/or previously diagnosed T2DM group and the non-hyperglycemic group. Fibrinolysis was assessed by measuring PAI-1 levels by ELISA. ResultsThe mean age was 59.4±16.1 years; 55.8% were male 54.1% of patients presented obesity, 38.1% had pre-existing T2DM and 50.8% had admission hyperglycemia and/or pre-existing T2DM. The patients with admission hyperglycemia and/or preexisting T2DM had higher PAI-1 compared with non-hyperglycemic patients [197.5 (128.8–315.9) vs 158.1 (113.4–201.4) ng/mL; p=0.031]. The glucose levels showed a positive correlation with PAI-1 levels (r=0.284, p=0.041). A multivariate logistic regression analysis showed association of PAI-1 level and hyperglycemia and pre-existing T2DM with severity of COVID-19. ConclusionPatients hospitalized for COVID-19 infection with preexisting T2DM or hyperglycemia detected during their hospitalization presented a greater increase in PAI-1 levels, which suggests that hyperglycemia contributes directly to the hypercoagulable state and probably a worse outcome from the patients.

Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Association of Plasminogen Activator Inhibitor-1 4G/5G and Angiotensin-Converting Enzyme I/D Polymorphisms with Recurrent Pregnancy Loss in Sudanese Women: A Case-Control study

The aim of our study was to investigate the relationship between the ACE I/D and PAI-1 4G/5G polymorphisms and RPL in Sudanese women. Methods and Results: A total of 232 people participated in this case-control study, including 119 women who had been diagnosed with RPL (Case group) and 113 healthy women (Control group). The case group (RPL) consisted of Sudanese women (mean age of 31.3+5.9 years) who had at least three unfavorable pregnancy outcomes. Women in the control group (Control) were matched by age (mean age of 30.3+5.4 years), had at least two healthy pregnancies, and had no history of unfavorable pregnancy outcomes or recurrent losses. Genomic DNA samples were isolated from the whole blood by using the GF-1 Blood DNA Extraction Kit (Vivantis Technologies Sdn. Bhd., Malaysia) according to the manufacturer`s protocol. The status of the PAI-1 4G/5G and ACE I/D polymorphism was determined by PCR. Analysis of the multiplicative and additive models for the ACE I/D polymorphism showed a significant risk of RPL with the carriage of the D allele (OR=2.07, 95% CI: 1.28-3.35, P=0.003) and the homozygous DD genotype (OR=2.40, 95% CI: 1.34-4.29, P=0.008). The multiplicative and additive models for the PAI-1 4G/5G polymorphism showed a significant risk of RPL with the carriage of the 4G allele (OR=3.11, 95% CI: 2.12-4.58, P=0.000) and the homozygous 4G/4G genotype (OR=3.09, 95% CI: 1.77-5.39, P=0.000). However, the carriage of risk-polymorphic markers, the ACE I/D and PAI-1 4G/5G polymorphisms, was not associated with the number of RPL. The combined carriage of the homozygous DD genotype and heterozygous ID genotype of the ACE I/D polymorphism with the homozygous 4G/4G genotype of the PAI-1 4G/5G polymorphism occurs significantly more often in RPL women than healthy women (P=0.000 and P=0.006, respectively). Carriage of the PAI-1 5G/5G genotype in healthy women was not associated with the ACE I/D polymorphism. Conclusion: Testing for the ACE I/D and PAI-1 4G/5G polymorphisms should be part of the standard examination for patients with RPL.

Plasminogen Activator Inhibitor-1 and Adiponectin Are Associated With Metabolic Syndrome Components.

We aimed to study the associations of adipocytokines, endothelial damage markers, and high-sensitivity C-reactive protein (hs-CRP) with metabolic syndrome (MetS) components. This cross-sectional study included 202 subjects categorized into MetS and No-MetS according to Harmonizing Adult Treatment Panel III. Subjects with MetS showed higher levels of proinflammatory molecules but significantly lower adiponectin levels than subjects with No-MetS. Among the studied adipocytokines, plasminogen activator inhibitor-1 (PAI-1) and adiponectin showed the strongest associations with most MetS components. PAI-1 was associated with MetS (odds ratio (OR) 1.107 (1.065-1.151), P < 0.0001), whereas adiponectin was inversely associated with MetS (OR 0.710 (0.610-0.825), P < 0.0001). Following adjustment by sex, age, body mass index, and 24-hour urinary sodium excretion in a multivariate analysis, the association of PAI-1 (OR 1.090 (1.044-1.137), P < 0.0001) and adiponectin (OR 0.634 (0.519-0.775), P < 0.0001) with MetS remained significant. Multivariate analyses supported a model in which systolic blood pressure (BP) could be predicted by PAI-1, hs-CRP, and matrix metalloproteinase 2 (R2 = 0.125; P = 0.04); diastolic BP (R2 = 0.218; P = 0.0001) and glucose (R2 = 0.074; P = 0.0001) could be predicted by PAI-1; waist circumference could be predicted by PAI-1 and hs-CRP (R2 = 0.28; P = 0.016). Receiver operating characteristic curve analysis showed that a PAI-1 concentration had the best sensitivity and specificity for discriminating subjects with MetS. PAI-1 and adiponectin rendered the most robust associations with MetS components in a general population, indicating that unfavorable adipose tissue performance is a key contributor to these metabolic anomalies. Further prospective analyses should allow establishing whether these adipocytokines can anticipate the progress of MetS and cardiovascular risk.

Association of Plasminogen Activator Inhibitor-1 and Cardiovascular Events Development in Patients with Prediabetes

Background. Plasminogen activator inhibitor-1(PAI-1) is a marker of endothelial dysfunction(ED) and a predictor of both the development of type 2 diabetes mellitus, and a cardiovascular event(CVE). Its role in the CVE development was sufficiently studied in patients without carbohydrate metabolism disorders, and understudied in patients with prediabetes.&#x0D; Aim: the research interest is the study of PAI-1 in patients with prediabetes and its effect on the CVE development.&#x0D; Materials and methods. The case-control study of 168 patients aged from 18 to 65 was carried out among the local population from January to December 2019.After clinical examination, patients were divided into 3 groups: group 1 (n=55)– patients with prediabetes and with CVE; group 2 (n=93) - patients with prediabetes and without CVE; the control group n=20.&#x0D; Results. Differences in PAI-1 level were found in groups 1 (Me=30718.6 pg/ml) and 2 (Me=24692.0 pg/ml; p≤0.001), even greater differences were found in both groups compared to the control one (p≤0.001).&#x0D; The correlation analysis has found in both group influence such IR indicators as fasting glucose, IR-HOMA index, glucagon, C-peptide to elevation of PAI-1. These findings indicate that with an elevation of the PAI-1 level, the concentration of fasting glucose, glucagon, C-peptide and scores of IR-HOMA index increase in both group.&#x0D; The Binary regression analysis has demonstrated, that an elevation of the PAI-1 biomarker increases the likelihood of CVE by 3.3 fold in patients with prediabetes (p≤0.01). In addition to, a model has been derived for assessing the risk of cardiovascular events in patients with prediabetes.&#x0D; Conclusions. Elevation of PAI-1 concentration is associated with insulin resistance which leads to ED, and further development risk of CVE in patients with prediabetes.

Association of Plasminogen Activator Inhibitor-1, intima media Thickness, and Insulin Resistance Indicators in Patients with the Risk of Type 2 Diabetes

Background. Changes in the vascular wall in patients with diabetes risk are currently poorly understood, however even at the stage of diabetes risks, endothelial dysfunction(ED) occurs. Aims: to study the relationship of insulin resistance(IR) indicators, ED biomarker PAI-1 level and intima media thickness(IMT) of the common carotid artery(cca) in patients with risk of type 2 diabetes mellitus(T2DM). Methods. An observational, cross-sectional study was conducted, including 176 individuals. There were 2 groups based on the FINDRISC scale: Group 1(n=136) low risk of DM2T(<12 points); and Group 2(n=40) high risk of DM2T(>12 points). Ultrasound measured of the right and left IMTcca value≥0.9 mm was considered as a marker of atherosclerosis. Results. Significant differences in the PAI-1 level were found between Group 1-29043.16±17780.11 pg/ml(Mean±SD) and Group 2-32608.14±19837.14 pg/ml; p=0.03. It was also found the predominance of IMT in Group 2(right IMTcca -0.90±0.15 mm;p=0.05, left IMTcca-0.91±0.14 mm;p=0.01) to compared Group 1. Correlation analysis found relationship between PAI-1, the right IMTcca(r=0.23; р=0.05), left IMTcca(r=0.32; р=0.05), and also presence of atherosclerosis (r=0.39; р=0.01) in patients with DM2T high risk. An increase in PAI-1 level affects the risk of development atherosclerosis by 2.9 fold, according to binary regression analysis. PAI-1 showed significant correlation with insulin, IR-HOMA index, С-peptide, HbA1c, and fasting glucose in group DM2T high risk. Conclusions. We found significant relationship between the ED biomarker PAI-1 with IMT and IR in patients with DM2T high risk. We suggest that IMT and IR increase in parallel with PAI-1 elevation, leading to increased ED and cardiovascular risk in these patients.

The association of PAI-1 with 24 h blood pressure in young healthy adults is influenced by smoking and alcohol use: The African-PREDICT study

Background and aimsThe association between plasminogen activator inhibitor-1 (PAI-1) and blood pressure is well established, but it is debatable whether raised PAI-1 levels precede or result from raised blood pressure. Furthermore, it is unclear whether this association already exists in the absence of overt hypertension and to what degree it is influenced by health behaviours. Our aim was to investigate the association of 24 h blood pressure with PAI-1 activity (PAI-1act) in a young, healthy cohort, and to assess the influence of alcohol consumption and smoking on these associations. Methods and resultsHealthy black and white men and women (aged 20–30 years, n = 1156) were cross-sectionally analysed. Statistical analysis was performed first split by ethnicity and sex and then by alcohol consumption and smoking. Regression analyses adjusted for age revealed positive associations of 24 h blood pressure with PAI-1act in most groups (p < 0.05). In multivariate-adjusted analyses, significance was lost in all groups except black men, who also had higher monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor antigen (vWFag) compared to white men (both p < 0.001). Analyses in black men, split by self-reported alcohol use and smoking, revealed 24 h blood pressure-PAI-1act associations only in alcohol users (24 h SBP [B = 4.22, p < 0.001], DBP [B = 2.04, p = 0.015] and PP [B = 2.18, p = 0.013]) and smokers (24 h SBP [B = 6.10, p < 0.001] and PP [B = 4.33, p = 0.001]). ConclusionOur findings support a positive association between 24 h blood pressure and PAI-1, particularly in individuals with higher MCP-1 and vWFag levels. Furthermore, smoking and alcohol consumption play an important role in modifying the association between blood pressure and PAI-1.

Association of plasminogen activator inhibitor-1 and low-density lipoprotein heterogeneity as a risk factor of atherosclerotic cardiovascular disease with triglyceride metabolic disorder: a pilot cross-sectional study.

We hypothesized that an increase in plasminogen activator inhibitor 1 (PAI-1) might reduce low-density lipoprotein (LDL) particle size in conjunction with triglyceride (TG) metabolism disorder, resulting in an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study was carried out as a hospital-based cross-sectional study in 537 consecutive outpatients (mean age: 64 years; men: 71%) with one or more risk factors for ASCVD from April 2014 to October 2014 at the Cardiovascular Center of Nihon University Surugadai Hospital. The estimated LDL-particle size was measured as relative LDL migration using polyacrylamide gel electrophoresis with the LipoPhor system.The plasma PAI-1 level, including the tissue PA/PAI-1 complex and the active and latent forms of PAI-1, was determined using a latex photometric immunoassay method. A multivariate regression analysis after adjustments for ASCVD risk factors showed that an elevated PAI-1 level was an independent predictor of smaller-sized LDL-particle in both the overall patients population (β=0.209, P<0.0001) and a subset of patients with a serum low-density lipoprotein cholesterol (LDL-C) level lower than 100 mg/dl (β=0.276, P<0.0001). Furthermore, an increased BMI and TG-rich lipoprotein related markers [TG, remnant-like particle cholesterol, apolipoprotein (apo) B, apo C-II, and apo C-III] were found to be independent variables associated with an increased PAI-1 level in multivariate regression models. A statistical analysis of data from nondiabetic patients with well-controlled serum LDL-C levels yielded similar findings. Furthermore, in the 310 patients followed up for at least 6 months, a multiple-logistic regression analysis after adjustments for ASCVD risk factors identified the percent changes of the plasma PAI-1 level in the third tertile compared with those in the first tertile as being independently predictive of decreased LDL-particle size [odds ratio (95% confidence interval): 2.11 (1.12/3.40), P=0.02]. The plasma PAI-1 levels may be determined by the degree of obesity and TG metabolic disorders. These factors were also shown to be correlated with a decreased LDL-particle size, increasing the risk of ASCVD, even in nondiabetic patients with well-controlled serum LDL-C levels.

Abstract MP017: Association of Change in Plasminogen Activator Inhibitor-1 Through Young Adulthood With Metabolic Disease in Middle Age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Circulating plasminogen activator inhibitor-1 (PAI-1) levels are elevated in obesity and diabetes mellitus (DM) in cross-sectional studies. Preclinical studies support a role for PAI-1 in obesity development and insulin signaling. To date, no studies have investigated the prospective association of PAI-1 in young adults with incident obesity and DM. Hypothesis: Higher PAI-1 concentrations and greater increases in PAI-1 during young adulthood are associated with higher incidence of obesity and diabetes. Methods: We performed an ancillary study in CARDIA measuring PAI-1 in plasma at exam year (Y) 7 and Y20 in a subset of 1200 participants (ppts) free of obesity and DM at Y7. Multivariable logistic regression was used to examine the association between PAI-1 at Y7 and change from Y7 to Y20 with incident obesity and diabetes by Y30. Covariates for adjustment included demographics (age, race, sex, center, education), lifestyle risk factors (physical activity, energy intake, smoking), metabolic traits (BMI, fasting glucose [for DM]), and Y7 PAI-1 level. Results: At Y7, ppts (32±4 years, 54% female, 37% black) had mean BMI 24.5±3 kg/m 2 , fasting glucose 89±8 mg/dL, and median PAI-1 14 (IQR: 8-24) ng/mL. Median change in PAI-1 from Y7 to Y20 was +10.0 ng/mL (IQR: +1.0-28.0 ng/dL). Each 1 standard deviation higher ln(PAI-1) at Y7 was associated with an adjusted hazards ratio for incident DM of 1.35 (95% CI: 1.09-1.67). Each 1 standard deviation greater increase in PAI-1 from Y7 to Y20 was associated with an adjusted odds ratio (OR) for incident obesity and DM of 1.21 (1.02-1.43) and 1.36 (1.10-1.68), respectively. When examined by quartiles, the highest (vs. lowest) quartile of Y7 to Y20 PAI-1 change was associated with an adjusted OR of 2.37 (1.33-4.21) for incident obesity and 3.11 (1.45-6.68) for incident DM by Y30, independent of Y7 BMI and PAI-1 (FIGURE) . Conclusions: Higher plasma PAI-1 levels and greater increases in PAI-1 during young adulthood are positively associated with incident obesity and DM by middle age.

Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

Association of plasminogen activator inhibitor-1 and vitamin D receptor expression with the risk of keloid disease in a Chinese population

Keloid disease (KD) is a benign fibroproliferative scarring condition of unknown etiopathogenesis. Plasminogen activator inhibitor-1 (PAI-1) and vitamin D receptor (VDR) have been shown to play important roles in the progression of tissue fibrosis; therefore, both these genes are potential susceptibility genes for KD. We aimed to determine whether the gene expression levels of PAI-1 and VDR are altered in Chinese KD patients. We measured the expression of PAI and VDR in human peripheral blood lymphocytes in 236 patients with keloid and 219 age- and sex-matched healthy controls by quantitative real-time polymerase chain reaction. We found that PAI-1 expression in peripheral blood lymphocytes was significantly higher in patients with KD than in control individuals (p < 0.0001), while VDR expression was significantly lower in KD patients than in control individuals (p < 0.0001). High levels of PAI-1 and low levels of VDR expression were significantly associated with an increased risk for KD. PAI-1 and VDR might play important roles in keloid development. Gene expression levels of PAI-1 and VDR may, therefore, be used as potential markers for the prediction of keloid development after scarring.

Plasminogen activator inhibitor-1 concentrations and bone mineral density in postmenopausal women with type 2 diabetes mellitus.

BackgroundWomen with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD). In experimental studies a potential role of plasminogen activator inhibitor-1 (PAI-1) in bone remodeling is suggested but studies in humans are lacking. This is a first study in humans investigating whether circulated levels of PAI-1 in postmenopausal women with T2DM are related to BMD and adiposity.MethodsAnthropometric variables, PAI-1 and insulin levels, serum lipids and bone turnover markers were measured in 127 postmenopausal women with T2DM. A total of 117 female patients were divided according to lumbar spine BMD measurements via dual-energy x-ray absorptiometry in three groups: 47 with osteopenia, 21 with osteoporosis and 49 with normal BMD.ResultsDiabetic patients with normal BMD had significantly higher BMI, greater waist circumference and lower bone turnover markers than diabetics with osteopenia and osteoporosis. PAI-1 was lower in diabetics with osteoporosis and osteopenia compared with diabetics with normal BMD. Multiple regression analysis revealed insulin, triglycerides levels, pyrilinks and beta blocker therapy to be the strongest predictors of PAI-1 levels. PAI-1 levels correlated with both L-BMD and hip BMD, but after adjustment for age and BMI association was no longer significant.ConclusionOur findings suggest that elevated PAI-1 levels are associated with higher BMD in obese diabetic patients but the possible implications of this finding and underlying mechanisms still remain unclear. Obviously, metabolic parameters, may affect both BMD and PAI-levels, and association of PAI-1 and BMD could be indirect. However, as pyrilinks is also independently and significantly negatively correlated to PAI-1 its direct involvement in bone metabolism is also plausible. Further investigations are needed to elucidate the nature of interaction of this matrix modulator in relation to energy and bone metabolism in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-016-0094-x) contains supplementary material, which is available to authorized users.

Abstract 43: Association of Plasminogen Activator Inhibitor-1 with Prevalent and Incident Obesity is Independent of Inflammatory Markers: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background: In experimental animal models, deficiency of plasminogen activator inhibitor-1 (PAI-1) protects against development of obesity. In addition, elevated circulating levels of PAI-1 are associated in cross-sectional studies with prevalent obesity in humans. However, no studies have investigated the prospective association between PAI-1 and incident obesity. Methods: Plasma PAI-1 levels were measured in a random sample of men and women at baseline (2000-2002) in the Multi-Ethnic Study of Atherosclerosis. Obesity was defined as body mass index (BMI) &gt; 30kg/m2. Incident obesity was identified at four follow-up exams (2002-2011) among those who were not obese at baseline. Logistic regression was used to examine the odds ratios (OR) and 95% confidence intervals (CI) of prevalent obesity at baseline. Cox proportional hazards regression was used to estimate hazard ratios (HR) for time to incident obesity. The covariates used for adjustment included baseline demographics (age, race, sex, center), lifestyle risk factors (physical activity, dietary energy intake, smoking status, alcohol consumption, education), and inflammatory markers (CRP and IL-6). Results: In 839 participants mean age was 59 years old; 59% and 47% of the cohort were female and white, respectively. At baseline, each standard deviation (SD) increase in log(PAI-1) level was associated with an odds ratio (OR) for adjusted prevalent obesity of 2.70 (95% CI: 2.21 - 3.30, p&lt;0.001. This association remained significant after further adjustment for IL-6 and CRP with OR 2.39 (95% CI: 1.94-2.94, p&lt;0.001). Over a median follow-up of 8.5 years, 16% of participants developed obesity. The multivariable adjusted hazard ratio for incident obesity was 1.36 (95% CI 1.09-1.69, p&lt;0.001) per 1 SD increase in log(PAI-1). (Table). Conclusions: Elevated PAI-1 levels are associated with prevalent and incident obesity. These findings are consistent with results from murine studies and provide evidence suggesting a potential role of PAI-1 in the pathogenesis of obesity.

Role of plasminogen activator inhibitor-1 in senescence and aging.

The average age of the US population continues to increase. Age is the most important determinant of disease and disability in humans, but the fundamental mechanisms of aging remain largely unknown. Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging. While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in kl/kl and N(ω)-nitro-l-arginine methyl ester-treated wild-type mice. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies.

Relation of PAI-1 and TPA genes polymorphisms to acute myocardial infarction and its outcomes in Egyptian patients.

Endogenous fibrinolysis is a protective mechanism against arterial thrombotic occlusion, which would otherwise lead to permanent tissue damage as acute myocardial infarction (AMI). We aimed to investigate the association of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (TPA) genes polymorphisms with myocardial infarction and its outcomes in Egyptian patients. 184 patients with AMI and 184 controls were included in the study. PAI-1 and TPA genes polymorphisms were analyzed by polymerase chain reaction. All patients were followed for AMI complications during their hospitalization. We found a significant association among TPA ID, II genotypes, and I allele and increased risk of AMI by 2.1, 3.2, and 1.9 fold, respectively. Also, the frequencies of PAI-1 4G/4G genotype and 4G allele were significantly increased in patients with AMI as compared to the control group. Furthermore, AMI patients with PAI-1 4G/4G genotype were significantly more likely to have morbidity and mortality complications as compared to AMI patients without complications (P = 0.00 and 0.048, respectively). We concluded that 4G/4G genotype and 4G allele of the PAI-1 gene are associated with risk of AMI and its morbidity. The PAI-1 4G/4G genotype is associated with mortality of AMI. There is also an association between TPA ID, II genotypes, and I allele with increased risk of AMI.

Type 1 plasminogen activator inhibitor as a common risk factor for cancer and ischaemic vascular disease: the EPICOR study

ObjectivesWe examined the association of plasminogen activator inhibitor-1 (PAI-1) levels with colorectal cancer, breast cancer, acute coronary syndrome (ACS) and ischaemic stroke.DesignNested case-cohort study.SettingThe European Prospective Investigation into Cancer and...

A Non-Lethal Traumatic/Hemorrhagic Insult Strongly Modulates the Compartment-Specific PAI-1 Response in the Subsequent Polymicrobial Sepsis

IntroductionPlasminogen activator inhibitor 1 (PAI-1) is a key factor in trauma- and sepsis-induced coagulopathy. We examined how trauma-hemorrhage (TH) modulates PAI-1 responses in subsequent cecal ligation and puncture (CLP)-induced sepsis, and the association of PAI-1 with septic outcomes.MethodsMice underwent TH and CLP 48 h later in three separate experiments. In experiment 1, mice were sacrificed pre- and post-CLP to characterize the trajectory of PAI-1 in plasma (protein) and tissues (mRNA). Post-CLP dynamics in TH-CLP (this study) and CLP-Only mice (prior study) were then compared for modulatory effects of TH. In experiment 2, to relate PAI-1 changes to outcome, mice underwent TH-CLP and were sampled daily and followed for 14 days to compare non-survivors (DEAD) and survivors (SUR). In experiment 3, plasma and tissue PAI-1 expression were compared between mice predicted to die (P-DIE) and to live (P-LIVE).ResultsIn experiment 1, an early post-TH rise of circulating PAI-1 was contrasted by a delayed (post-TH) decrease of PAI-1 mRNA in organs. In the post-CLP phase, profiles of circulating PAI-1 were similar between TH-CLP and CLP-Only mice. Conversely, PAI-1 mRNA declined in the liver and heart of TH-CLP mice versus CLP-Only. In experiment 2, there were no DEAD/SUR differences in circulating PAI-1 prior to CLP. Post-CLP, circulating PAI-1 in DEAD was 2–4-fold higher than in SUR. PAI-1 increase heralded septic deaths up to 48 h prior but DEAD/SUR thrombomodulin (endothelial injury marker) levels were identical. In experiment 3, levels of circulating PAI-1 and its hepatic gene expression were higher in P-DIE versus P-LIVE mice and those increases closely correlated with liver dysfunction.ConclusionsTrauma modulated septic PAI-1 responses in a compartment-specific fashion. Only post-CLP increases in circulating PAI-1 predicted septic outcomes. In posttraumatic sepsis, pre-lethal release of PAI-1 was mostly of hepatic origin and was independent of endothelial injury.

Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters in Malaysian subjects

The plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat insertion/deletion polymorphisms might be genetic determinations of increased or decreased of their plasma activities. The aim of this study was to investigate the association of plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat I/D polymorphisms with metabolic syndrome parameters in normal Malaysian subjects and to assess the impact of these polymorphisms on their plasma activities and antigens. The genetic polymorphisms were genotyped in 130 normal subjects. In addition, the plasma activities and antigens of plasminogen activator inhibitor-1 and tissue plasminogen activator as well as levels of insulin, glucose, and lipid profile at fasting state were investigated. The subjects with homozygous 4G/4G showed association with an increased triglyceride (p = 0.007), body mass index (p = 0.01) and diastolic blood pressure (p = 0.03). In addition, the plasminogen activator inhibitor-1 4G/5G polymorphism modulates plasma plasminogen activator inhibitor-1 activity and antigen and tissue plasminogen activator activity (p = 0.002, 0.014, 0.003) respectively. These results showed that, the plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters, plasminogen activator inhibitor-1 and tissue plasminogen activator activities in Malaysian subjects, and may serve to increase the risk of type 2 diabetes and cardiovascular disease in Malaysian subjects.

Association of plasminogen activator inhibitor-1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects

BackgroundIncreased plasma plasminogen activator inhibitor-1 (PAI-1) activity and decreased tissue plasminogen activator (tPA) activity could be considered a true component of the metabolic syndrome (MetS) associated with an increased risk of developing cardiovascular diseases (CVD) and fibrinolytic abnormalities. The aim of this study was to investigate the association of tPA and its inhibitor PAI-1 with type 2 diabetes (T2D) and MetS and interrelationship between PAI-1and tPA activities and antigens in Malaysian T2D and normal subjects.MethodsThe plasma activities and antigens of PAI-1 and tPA and the levels of the tPA/PAI-1 complex as well as serum insulin, parameter of the coronary risk panel and plasma glucose at fasting state were studied in 303 T2D subjects (227 with MetS and 76 without MetS), 131 normal non-diabetic non-metabolic subjects and 101 non-diabetic MetS subjects.ResultsThe PAI-1 activity was higher in subjects with T2D with MetS (P = 9.8 × 10-19) and non-diabetic subjects with MetS (P = 3.0 × 10-15), whereas the tPA activity was lower in T2D with MetS (P = 0.003) as compare to normal subjects. Plasma tPA antigen levels were higher in subjects with T2D with MetS (P = 8.9 × 10-24), T2D without MetS (P = 1.3 × 10-13) and non-diabetic MetS subjects (P = 0.002). The activity and antigen of PAI-1 in normal subjects were related to insulin resistance (P = 2.2 × 10-4; 0.007). Additionally, the PAI-1 activity was associated with an increased waist circumference (P = 2.2 × 10-4) and decreased HDL-c (P = 0.005), whereas the tPA activity was associated with decreased FBG (P = 0.028). The highest correlation was between PAI-1 activity and its antigen (R2 = 0.695, P = 1.1 × 10-36) in diabetic subjects. The tPA activity negatively correlated with its antigen (R2 = -0.444, P = 7.7 × 10-13) in normal subjects and with the PAI-1 activity and antigen (R2 = -0.319, P = 9.9 × 10-12; R2 = -0.228, P = 3.4 × 10-6) in diabetic subjects.ConclusionsPAI-1 and tPA activities and antigens were associated with diabetes and MetS parameters in Malaysian subjects.

Relationship between resistin and aPAI‐1 levels with insulin resistance in Saudi children

Association of resistin with insulin resistance (IR) in humans is still controversial and few studies have investigated the association of plasminogen activator inhibitor-1 (PAI-1) with IR in children. The purpose of the present study was therefore to evaluate serum levels of resistin and active PAI-1 (aPAI-1) in Saudi children and their association with the various obesity-related complications. In this cross-sectional study, 73 boys and 77 girls with varying body mass index (BMI) were recruited. They were assessed for anthropometric measures and fasting serum levels of glucose, insulin, lipid profile, resistin, angiotensin II (ANG II) and aPAI-1. Resistin was positively correlated with hips (r = 0.33, P < 0.01), waist (r = 0.23, P < 0.05) and BMI (r = 0.33, P < 0.01). The association of resistin with the markers of obesity was also significant in girls but lost significance in boys. aPAI-1 was positively correlated with total cholesterol (r = 0.24; P < 0.01), triglycerides (r = 0.2, P < 0.05), HOMA-IR (r = 0.26, P < 0.01) and insulin (r = 0.26, P < 0.01). The significant association of aPAI-1 with IR was also true in girls but lost significance in boys. Resistin is not correlated with IR and further studies are needed to explore the role of resistin especially in childhood obesity. In contrast, increased levels of PAI-1 may contribute to the risk of cardiovascular diseases related to obesity and insulin resistance in children. The observed gender-related differences in the association between resistin, aPAI-1 with obesity markers and IR could be attributed to sexual dimorphism in body fat distribution.