Plasma Plasminogen Activator Inhibitor-1 Research Articles

Different patterns of fibrinolytic abnormalities and lipid profile in hypothyroid and hyperthyroid patients

Altered fibrinolytic parameters and serum lipid profile are strongly related to thyroid dysfunction. To investigate the patterns of the fibrinolytic abnormalities and serum lipid profile in the hypo- and hyperthyroid patients. We also took an aim at studying the relationships between free T4 levels (FT4) and these parameters. Hyperthyroid (n = 30), hypothyroid (n = 20) patients and euthyroid control subjects (n = 30) were evaluated for several fibrinolytic parameters including plasma plasminogen activator inhibitor-1 (PAI-1) and D-dimer (D-D). Serum lipid profile and lipoprotein(a) (Lp(a)) were also measured. We found different patterns of fibrinolytic abnormalities and lipid profile in hypo- and hyperthyroid patients. The hypothyroid patients had low plasma PAI-1 levels and high D-D values as compared to hyperthyroid patients (p < 0.001) and euthyroid control subjects (p < 0.05 and 0.001, respectively). In sharp contrast, the hyperthyroid patients had high plasma PAI-1 levels (p < 0.001) but without concomitant change in plasma D-D values, as compared to the euthyroid control subjects. Hypothyroidism was associated with high total cholesterol, triglycerides, LDL-C and Lp(a) levels and low HDL-C levels as compared to both hyperthyroid and euthyroid states (p < 0.001). FT4 levels were correlated positively with HDL-C but negatively with total cholesterol, triglycerides, LDL-C and Lp(a) levels in both hypo- and hyperthyroid patients. Also FT4 levels were correlated positively with PAI-1 but negatively with D-D in both hypo- and hyperthyroid patients (p < 0.02, 0.01, 0.001 and 0.03 respectively). We found hyperfibrinolytic, and hypofibrinolytic patterns in hypothyroid, hyperthyroid patients, respectively. The hypothyroid patients had atherogenic lipid profile. These variations indicate possible pathophysiologic roles for thyroid hormones in the regulation of the fibrinolytic system and lipid profile. Mechanisms of these variations are open for future investigations.

P 3: Insulin sensitivity and related atherogenic conditions in ischemic stroke: comparison between type 2 diabetics and nondiabetics

Background and aims The role and importance of insulin sensitivity (IS) and related atherogenic conditions in ischemic stroke have not yet been elucidated. Therefore, our study was aimed to analyze (a) IS and plasma insulin (PI) (b) lipoproteins (c) plasminogen activator inhibitor 1 (PAI-1) levels (d) inflammatory markers, hs-C reactive protein (hs CRP) and interleukin-6 (IL-6) levels (e) abdominal obesity, in 40 type 2 diabetics (T2D) with ischemic stroke (group A), 35 T2D without ischemic stroke (group B), 35 nondiabetics with ischemic stroke (group C) and 34 healthy controls (group D). Material and Methods Ischemic stroke was confirmed by clinical and neuroimaging criteria. IS levels were determined by the frequently sampled intravenous glucose tolerance (FSIGT) test with minimal model analysis (Si index). Total cholesterol, HDL-cholesterol (HDL-c), and tryglicerides concentracion were determined with the chromatography metod. LDL-cholesterol (LDL-c) concentrations were calculated using the Friedewald formula. Plasma PAI-1 activity was determined by plasminogen chromogenic plasmin substrate assay. Hs-CRP was determined by Olympus Analyzer and interleukin 6 (IL-6) levels were measured by ELISA method. Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest. Results Si levels were significantly lower in group A vs B (1.15+/−0.46 vs 2.81+/−0.65 min-1/mU/lx104; p Conclusion Our results demonstrated that decreased IS are associated with increased LDL-c, decreased PAI-1, together with higher hs-CRP, IL-6 levels and waist circumference, both in T2D and nondiabetics. These results imply that decreased IS in association with compensatory hyperinsulinemia, underlying the development of the ischemic stroke, through potentiation of dislipidemia, hypofibrinolisis, low-grade inflammation and abdominal obesity.

Early Insulin Glycemic Control Combined With tPA Thrombolysis Reduces Acute Brain Tissue Damages in a Focal Embolic Stroke Model of Diabetic Rats

Therapeutic effects of early insulin glycemic control for poststroke hyperglycemia in combination with tissue-type plasminogen activator (tPA) thrombolytic therapy have not yet been studied but are of great clinical interest. In this study, we tested the effects of insulin plus tPA combination in a model of focal embolic stroke in Type I diabetic rats. Streptozotocin was used to produce Type I diabetes in male Wistar rats for 6 weeks and then embolic focal strokes were induced. All rats were treated with insulin or saline at 1 hour followed by tPA or saline at 1.5 hour after stroke. Mortality, infarction, hemispheric swelling, hemorrhagic transformation, and perfusion defects were examined at 24 hours after stroke. Total plasma plasminogen activator inhibitor-1 antigen and activity levels were measured before stroke and 1.5, 3, and 6 hours after stroke by ELISA. Early insulin glycemic control alone or tPA thrombolysis alone had no significant effects on ischemic infarction. However, early insulin glycemic control combined with tPA significantly reduced brain infarction and swelling, ameliorated tPA-associated hemorrhagic transformation, and improved plasma perfusion at 24 hours after stroke. We also found that the combination significantly decreased plasma plasminogen activator inhibitor-1 antigen level at 6 hours and plasminogen activator inhibitor-1 activity at 1.5 and 6 hours after stroke. Early insulin glycemic control may be beneficial in combination with tPA thrombolysis for ischemic stroke with diabetes mellitus or poststroke hyperglycemia.

Significantly increased concentration of soluble urokinase-type plasminogen activator receptor in the blood of patients with pelvic inflammatory disease

BackgroundTo determine expression levels of urokinase-type plasminogen activator (uPA), soluble urokinase-type plasminogen activator receptor (suPAR), plasminogen activator inhibitor-1 (PAI-1) in plasma and to identify gene polymorphisms specific to patients with pelvic inflammatory disease (PID) and healthy controls. MethodsEnzyme-linked immunosorbent assay and polymerase chain reaction–restriction fragment length polymorphism were used to measure plasma levels and polymorphisms in uPA, suPAR, and PAI-1 among seventy healthy controls and 64 PID patients before and after they received routine treatment protocols. ResultsThe levels of plasma uPA (ng/ml) and soluble suPAR (pg/ml) were significantly increased in PID patients (uPA: 0.57±0.03; suPAR: 1372.04±68.20) when compared to that in normal controls (uPA: 0.55±0.06, p=0.002; suPAR: 1192.46±51.98, p=0.04); moreover, suPAR decreased significantly after treatment when compared to levels noted in the same patients (1220.06±58.14; p=0.003) after they received treatment. The increased expression of suPAR was significantly correlated with WBC counts (r=0.382, p=0.002, n=64) in blood as well as the plasma levels of CRP (r=0.441, p<0.0001, n=64) and uPA (r=0.426, p<0.0001, n=64) of PID patients prior to receiving treatment. ConclusionsIncreased plasma suPAR could be a biological marker for the diagnosis of PID and may reflect a new focus in targeted therapy for pelvic inflammatory disease.

C0112 Activated protein c resistance in Tunisian patients with thromboembolic complication or spontaneous recurrent miscarriage

Background: Particulate air pollution has been associated with increased risk of cardiovascular and pulmonary diseases. However, the underlying mechanisms are not fully understood. Methods: Here, we exposed mice with repeated doses of diesel exhaust particles (DEP, 15 μg/animal) every 2nd day for 6 days (a total of 4 exposures), and measured several cardiopulmonary endpoints 48 h after the end of the treatments. Moreover, the potential protective effect of curcumin (the yellow pigment isolated from turmeric) on DEP-induced cardiopulmonary toxicity was assessed. Results: DEP exposure increased macrophage and neutrophil numbers, tumor necrosis factor α (TNF α) in the bronchoalveolar lavage (BAL) fluid, and enhanced airway resistance to methacoline measured invasively using Flexivent. DEP also significantly increased plasma C-reactive protein (CRP) and TNFα concentrations, systolic blood pressure (SBP) as well as the pial arteriolar thrombosis. It also significantly enhanced the plasma D-dimer and plasminogen activator inhibitor-1 (PAI-1). Pretreatment with curcumin by oral gavage (45 mg/kg) 1 h before exposure to DEP significantly prevented the influx of inflammatory cells and the increase of TNF α in BAL, and the increased airway resistance caused by DEP. Likewise, curcumin prevented the increase of SBP, CRP, TNF α, D-dimer and PAI-1. The thrombosis was partially but significantly mitigated. Comment: In conclusion, repeated exposure to DEP induced lung and systemic inflammation characterized by TNFα release, increased SBP, and accelerated coagulation. Our findings indicate that curcumin is a potent anti-inflammatory agent that prevents the release of TNFα and protects against the pulmonary and cardiovascular effects of DEP.

Protective effect of Danhong injection on cerebral ischemia–reperfusion injury in rats

Ethnopharmacological relevanceDanhong injection (DH), a Chinese medical product, is used extensively for the treatment of cerebrovascular diseases such as acutely cerebral infarction in clinic. Aim of the studyTo explore the protective effect and the relevant mechanisms of DH on cerebral ischemia–reperfusion (I/R) injury. Materials and methodsCerebral I/R injury was induced through four-vessel occlusion (4-VO) or middle cerebral artery occlusion (MCAO). Adult male SD rats were randomly divided into six kinds of groups: normal control group, sham-operated group, I/R injury group, DH-treated groups at doses of 0.5ml/kg, 1.0ml/kg and 2.0ml/kg. The effects of DH on murine neurological deficits and cerebral infarct volume, 6-keto-prostagladin F1α (6-keto-PGF1α) level, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in brain tissue, as well as the activities of plasma tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) after I/R were evaluated. Moreover, the expressions of Bcl-2 and Bax protein were detected by immunohistochemistry. ResultsThere was no significant difference between the control group and the sham-operated group based on the measurement indicators. Compared with the vehicle-treated group, rats treated with DH showed dose dependent reductions in brain infarction size, and improvement of neurological outcome. The level of 6-keto-PGF1α and the activities of SOD and plasma t-PA were enhanced significantly, whereas the level of MDA and the activity of plasma PAI were declined significantly. The immunohistochemical staining results also revealed that the expression of Bcl-2 protein was up-regulated and that of Bax protein was down-regulated when exposed to DH. ConclusionDH demonstrates a strong ameliorative effect on cerebral I/R damage in rats by its anticoagulant, antithrombotic, antifibrinolytic and antioxidant activities. Furthermore, suppressing apoptosis through regulating Bcl-2 and Bax protein expressions should be another potential mechanism by which DH exerts its neuroprotective function.

Gender-Specific Alterations in Fibrin Structure Function in Type 2 Diabetes: Associations with Cardiometabolic and Vascular Markers

Diabetes is associated with increased incidence of atherothrombotic disease. The fibrin network forms the backbone of the arterial thrombus, and fibrin clot structure determines predisposition to cardiovascular events. The aim of the study was to investigate fibrin clot structure/fibrinolysis in the largest type 2 diabetes cohort and analyze associations with cardiometabolic risk factors and vascular pathology. Clot structure/fibrinolysis was assessed in 875 participants of the Edinburgh Type 2 Diabetes Study [age, 68 (range, 60-75) yr; 450 males] by turbidimetric assays, and clots were visualized by confocal microscopy. Four parameters of clot structure/fibrinolysis were analyzed, and plasma levels of fibrinogen and plasminogen activator inhibitor-1 were studied by Clauss assay and ELISA, respectively. Clot maximum absorbance was increased in females compared with males (0.37 ± 0.005 and 0.34 ± 0.005 arbitrary unit, respectively; P < 0.001), and took longer to lyse (803 ± 20 and 665 ± 12 sec, respectively; P < 0.001). These gender differences in clot structure and fibrinolysis were still evident after correcting for fibrinogen and plasminogen activator inhibitor-1 plasma levels. A prothrombotic fibrin structure profile was associated with increased body mass index and low levels of high-density lipoprotein in women and with inadequate diabetes control in men. Clot formation time was related to previous cardiac ischemic events in both men and women after adjusting for traditional risk factors [odds ratio, 1.22 (95% confidence interval, 1.07, 1.38); and 1.33 (1.15, 1.50), respectively], and prothrombotic clots were associated with low ankle brachial index, renal impairment, and smoking, regardless of gender. Women with type 2 diabetes have compact clots with compromised fibrinolysis compared with men. There are gender-specific associations between clotting parameters and cardiometabolic risk factors in this population, whereas vascular abnormalities, impaired renal function, and smoking are associated with prothrombotic clot structure profile regardless of gender.

The influence of abdominal visceral fat on inflammatory pathways and mortality risk in obstructive lung disease

Low-grade systemic inflammation, particularly elevated IL-6, predicts mortality in chronic obstructive pulmonary disease (COPD). Although altered body composition, especially increased visceral fat (VF) mass, could be a significant contributor to low-grade systemic inflammation, this remains unexplored in COPD. The objective was to investigate COPD-specific effects on VF and plasma adipocytokines and their predictive value for mortality. Within the Health, Aging, and Body Composition (Health ABC) Study, an observational study in community-dwelling older persons, we used propensity scores to match n = 729 persons with normal lung function to n = 243 persons with obstructive lung disease (OLD; defined as the ratio of forced expiratory volume in 1 s to forced vital capacity < lower limit of normal). Matching was based on age, sex, race, clinic site, BMI, and smoking status. Within this well-balanced match, we compared computed tomography-acquired visceral fat area (VFA) and plasma adipocytokines, analyzed independent associations of VFA and OLD status on plasma adipocytokines, and studied their predictive value for 9.4-y mortality. Whereas whole-body fat mass was comparable between groups, persons with OLD had increased VFA and higher plasma IL-6, adiponectin, and plasminogen activator inhibitor 1 (PAI-1). Both OLD status and VFA were independently positively associated with IL-6. Adiponectin was positively associated with OLD status but negatively associated with VFA. PAI-1 was no longer associated with OLD status after VFA was accounted for. Participants with OLD had increased risk of all-cause, respiratory, and cardiovascular mortality, of which IL-6 was identified as an independent predictor. Our data suggest that excessive abdominal visceral fat contributes to increased plasma IL-6, which, in turn, is strongly associated with all-cause and cause-specific mortality in older persons with OLD.

Fructose Rich Diet-Induced High Plasminogen Activator Inhibitor-1 (PAI-1) Production in the Adult Female Rat: Protective Effect of Progesterone

The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4-FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production.

Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

Antithrombotic Properties of Water-Soluble Carbon Monoxide-Releasing Molecules

We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide-releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined. CORM-A1 (10-30 µmol/kg, i.v.), in a dose-dependent fashion, significantly decreased weight of electrically induced thrombus in rats, whereas CORM-3 inhibited thrombosis only at the highest dose used (30 µmol/kg). CORM-A1 showed a direct and stronger inhibition of platelet aggregation than CORM-3 in healthy rats, both in vitro and in vivo. The antiaggregatory effect of CORM-A1, but not CORM-3, correlated positively with weight of the thrombus. Concentration of active plasminogen activator inhibitor-1 in plasma also decreased in response to CORM-A1, but not to CORM-3. Neither CORM-A1 nor CORM-3 had an effect on plasma concentration of active tissue plasminogen activator. CORM-3, but not CORM-A1, decreased the concentration of fibrinogen, fibrin generation, and prolonged prothrombin time. Similarly, laser-induced venous thrombosis observed intravitally via confocal system in green fluorescent protein mice was significantly decreased by CORMs. Although both CORM-A1 and CORM-3 (30 µmol/kg) decreased platelets accumulation in thrombus, only CORM-A1 (3-30 µmol/kg) inhibited platelet activation to phosphatidylserine on their surface. CORM-3 and CORM-A1 inhibited thrombosis in vivo, however CORM-A1, which slowly releases carbon monoxide, and displayed a relatively weak hypotensive effect had a more pronounced antithrombotic effect associated with a stronger inhibition of platelet aggregation associated with a decrease in active plasminogen activator inhibitor-1 concentration. In contrast, the fast CO releaser CORM-3 that displayed a more pronounced hypotensive effect inhibited thrombosis primarily through a decrease in fibrin generation, but had no direct influence on platelet aggregation and fibrynolysis.

Protective Effect of Curcumin on Pulmonary and Cardiovascular Effects Induced by Repeated Exposure to Diesel Exhaust Particles in Mice

Particulate air pollution has been associated with increased risk of cardiopulmonary diseases. However, the underlying mechanisms are not fully understood. We have previously demonstrated that single dose exposure to diesel exhaust particle (DEP) causes lung inflammation and peripheral thrombotic events. Here, we exposed mice with repeated doses of DEP (15µg/animal) every 2nd day for 6 days (a total of 4 exposures), and measured several cardiopulmonary endpoints 48 h after the end of the treatments. Moreover, the potential protective effect of curcumin (the yellow pigment isolated from turmeric) on DEP-induced cardiopulmonary toxicity was assessed. DEP exposure increased macrophage and neutrophil numbers, tumor necrosis factor α (TNF α) in the bronchoalveolar lavage (BAL) fluid, and enhanced airway resistance to methacoline measured invasively using Flexivent. DEP also significantly increased plasma C-reactive protein (CRP) and TNF α concentrations, systolic blood pressure (SBP) as well as the pial arteriolar thrombosis. It also significantly enhanced the plasma D-dimer and plasminogen activator inhibitor-1 (PAI-1). Pretreatment with curcumin by oral gavage (45 mg/kg) 1h before exposure to DEP significantly prevented the influx of inflammatory cells and the increase of TNF α in BAL, and the increased airway resistance caused by DEP. Likewise, curcumin prevented the increase of SBP, CRP, TNF α, D-dimer and PAI-1. The thrombosis was partially but significantly mitigated. In conclusion, repeated exposure to DEP induced lung and systemic inflammation characterized by TNFα release, increased SBP, and accelerated coagulation. Our findings indicate that curcumin is a potent anti-inflammatory agent that prevents the release of TNFα and protects against the pulmonary and cardiovascular effects of DEP.

Alterations in the Common Pathway of Coagulation During Weight Loss Induced by Gastric Bypass in Severely Obese Patients

The objective of this study was to establish the relationship between the plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (ATIII), fibrinogen, and white blood cell (WBC) levels in severely obese patients. We analyzed various plasma parameters implicated in the intrinsic and extrinsic coagulation pathway from 34 severely obese patients before and 1, 6, and 12 months after gastric bypass. In obese people, ATIII, fibrinogen, and WBC levels were in the upper limit of the normal range, and all were higher and significantly different from nonobese people. After bariatric surgery, the ATIII level continued to be high during the first month and increased until 12 months, while fibrinogen decreased only at that time. PAI-1 plasma protein and PAI-1 mRNA levels in liver and adipose tissue show similar profiles and had a strong positive correlation (r = 0.576, P = 0.0003 in liver; r = 0.433, P = 0.0004 in adipose tissue). They were higher in obese patients compared with nonobese control, but tended to recover normal values 1 month after surgery. Thus, the liver and adipose tissue could be an important source of PAI-1 protein in plasma. Gastric bypass surgery leads to a normalization of the hematological profile and a decrease in PAI-1 levels, which entails a decrease of risk for thromboembolism in severely obese.

Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults

Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type and urokinase-type plasminogen activator. A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to enhance the plasma levels of PAI-1. In particular, the 4G allele (guanosine deletion) has been linked with increased plasma PAI-1 levels, which may lead to impaired activity of the fibrinolytic system, thus increasing the incidence of thrombotic events. The aim of this case-control study was to analyze whether variants of the PAI-1 promotor genotype 4G/4G, 4G/5G and 5G/5G, in particular the 4G/5G-variant, constitute an independent risk factor of cerebral venous thrombosis (CVT). A total of 136 consecutive patients with proven CVT were compared to 1,054 DNA specimens of healthy controls from a population-based cohort. PAI-1 promotor polymorphisms were evaluated using polymerase chain reaction. No significant association of CVT with PAI-1 4G/5G was found in either the additive (OR 1.04; 95 % CI 0.78-1.38) or in the dominant model (OR 1.24; 95 % CI 0.72-2.13). Also, the prevalence of the other genotypes (4G/4G and 5G/5G) in patients was not significantly different from controls. When considering the variants of the PAI-1 promoter genotype in combination with known genetical thrombophilias, no differences were found either. As was expected, the prothrombin (G20210A) genotype was confirmed as an independent risk factor for CVT. We conclude that the 4G allele of the PAI-1 polymorphism does not increase the risk of CVT in adults.

Propolis and its constituent chrysin inhibit plasminogen activator inhibitor 1 production induced by tumour necrosis factor-α and lipopolysaccharide

SummaryPropolis is thought to help prevent thrombotic and related cardiovascular diseases in humans, but this has not yet been definitively demonstrated. Elevated levels of plasma plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis, predisposes individuals to a risk of developing thrombotic diseases. Plasma PAI-1 increases under inflammatory conditions such as infection, obesity and atherosclerosis. Maintaining physiological PAI-1 levels in plasma might represent a promising intervention for treating various diseases. The present study examines the effects of propolis and its components including flavonoids and derivatives of benzoic, cinnamic and quinic acids, on the increase in PAI-1 induced by inflammation. Propolis inhibited the increase in PAI-1 induced by tumour necrosis factor (TNF)-α in HUVEC culture medium. We also showed that the flavonoid chrysin is an active constituent. Both propolis and chrysin inhibited the increase in PAI-1 induced by LPS in mouse plasma. Thus propolis and its constituent, chrysin, inhibited PAI-1 production. The present findings confirmed the potential of propolis and its constituents in treating or preventing thrombotic disorders, or as an antithrombotic food supplement.

Plasma Plasminogen Activator Inhibitor-1 Is Associated with End-Stage Proliferative Diabetic Retinopathy in the Northern Chinese Han Population

Objective. To identify predictors of end-stage proliferative diabetic retinopathy (PDR) in a cohort of individuals with type 2 diabetes mellitus (T2DM) from the Northern Chinese Han population. Methods. We investigated characteristics of 153 consecutive diabetic patients with end-stage PDR (62 males, 91 females), 123 consecutive PDR patients without end-stage PDR (48 males, 75 females), and 151 normal subjects (63 males, 88 females). Only one eye of each patient or healthy subject was included in this study. Univariate logistic regression models and multivariate logistic regression models were constructed to evaluate the predictors of end-stage PDR. Results. In univariate analysis, systolic blood pressure, diastolic blood pressure, duration of diabetes, family history of T2DM, and plasminogen activator inhibitor-1 (PAI-1) were significently associated with end-stage PDR. After multivariate analysis, family history of T2DM, plasma PAI-1 levels, smoking, and duration of diabetes were four positive predictors associated with end-stage PDR. Conclusions. Higher plasma levels of PAI-1 were associated with end-stage PDR in the Northern Chinese Han population with T2DM.

Effect of Pioglitazone on the Fructose-Induced Abdominal Adipose Tissue Dysfunction

Aim. To test the potential role of PPARγ in the endocrine abdominal tissue dysfunction induced by feeding normal rats with a fructose rich diet (FRD) during three weeks. Methodology. Adult normal male rats received a standard commercial diet (CD) or FRD, (10% in drinking water) without or with pioglitazone (PIO) (i.p. 0.25 mg/Kg BW/day; CD-PIO and FRD-PIO). Thereafter, we measured circulating metabolic, endocrine, and oxidative stress (OS) markers, abdominal adipose tissue (AAT) mass, leptin (LEP) and plasminogen activator inhibitor-1 (PAI-1) tissue content/expression, and leptin release by isolated adipocytes incubated with different concentrations of insulin. Results. Plasma glucose, insulin, triglyceride, TBARS, LEP, and PAI-1 levels were higher in FRD rats; PIO coadministration fully prevented all these increments. AAT adipocytes from FRD rats were larger, secreted a higher amount of LEP, and displayed decreased sensitivity to insulin stimulation; these effects were significantly ameliorated by PIO. Whereas AAT LEP and PAI-1 (mRNA) concentrations increased significantly in FRD rats, those of insulin-receptor-substrate- (IRS-) 1 and IRS-2 were reduced. PIO coadministration prevented FRD effects on LEP, PAI-1, and IRS-2 (fully) and IRS-1 (partially) mRNAs in AAT. Conclusion. PPARγ would play a relevant role in the development of the FRD-induced metabolic-endocrine dysfunction.

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): Crossover pilot study (J-VICTORIA study)

BackgroundNo previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters.MethodsTwenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured.ResultsThe mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin.ConclusionsCGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin.Trial registrationUMIN000007687

Effects of Valsartan on Fibrinolysis in Hypertensive Patients With Metabolic Syndrome

The purpose of this study was to analyze the effect of valsartan on abnormal adipocyte metabolism and prothrombotic state in hypertensive patients with metabolic syndrome (MetS). We conducted a multicenter, prospective, randomized, parallel-group controlled trial in 150 hypertensive patients with MetS. They were randomly assigned to receive either 80-160 mg valsartan per day (valsartan group, n=79) or other conventional treatment without a renin-angiotensin system (RAS) inhibitor (non-RAS inhibitor group, n=71). After 1 year, there were no significant differences between the 2 groups in the changes in systolic and diastolic blood pressures (valsartan: 153±15/86±15 to 138±16/77±12 mmHg; non-RAS inhibitor: 150±14/82±15 to 137±15/76±10 mmHg). There was a significant difference in the change in the levels of plasminogen activator inhibitor-1 (PAI-1) between the 2 groups after 1 year (valsartan: 3.7±3.2 ng/ml; non-RAS inhibitor: 5.8±3.3 ng/ml, P=0.04). There was no significant difference between groups in the change in the concentration of adiponectin after 1 year (valsartan: 0.3±0.4 µg/ml; non-RAS inhibitor: 0.9±0.4 µg/ml, P=0.22). The animal study showed aortic PAI-1 protein expression was reduced in double knockout mice of angiotensin II type 1a receptor and apolipoprotein E (apoE) compared with the apoE knockout mice. Valsartan reduced plasma PAI-1 levels compared to non-RAS inhibitor in hypertensive patients with MetS, which suggests it may be useful for improving fibrinolytic function.

A history of early stent thrombosis is associated with prolonged clot lysis time

It has been demonstrated that formation of compact plasma fibrin clots resistant to plasmin-mediated lysis characterises patients following in-stent thrombosis (IST). The relationship between defective fibrinolysis, reflected as prolonged clot lysis time (CLT) and IST is unclear. We sought to investigate whether patients with acute and subacute IST have impaired fibrinolytic capacity. We studied 41 definite IST patients, including 15 with acute and 26 with subacute IST experienced 2-73 months prior to enrollment, versus 41 controls matched for demographics, cardiovascular risk factors, concomitant treatment and angiographic/stent parameters. CLT, reflecting lysis of a tissue factor-induced plasma clot by exogenous tissue plasminogen activator, together with plasminogen activator inhibitor-1 (PAI-1) antigen and activity, thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and activity, thrombomodulin (TM), plasminogen and α2-antiplasmin (α2AP) were measured. There were no inter-group differences in angiographic parameters, indication to the first PCI, culprit vessel or a type of stent. Patients with IST had 11% longer CLT (p=0.005) and 13% higher PAI-1 antigen (p=0.04) compared to controls. There were positive correlations in both groups between CLT and PAI-1 antigen and TAFI activity (all p<0.001). Multiple regression analysis showed that CLT (odds ratio [OR]=1.04 per 1 minute, 95% CI 1.01-1.08, p=0.02) and platelet count (OR=1.01 per 1,000/μl, 95% CI 1.00-1.02, p=0.034) were independent predictors of IST (R(2)=0.28, p<0.05). Concluding, impaired fibrinolytic potential, that is in part determined by plasma PAI-1 antigen and TAFI activity, characterises patients with a history of acute and subacute IST, which might help identify patients at higher risk of IST.