Plasminogen Activator Inhibitor-1 Gene Research Articles

Effect of aminoguanidine on plasminogen activator inhibitor-1 and receptor of advanced glycation endproduct in the liver of streptozotocin-induced diabetic rats

Objectives: Advanced glycation end products (AGEs) play an important role in the development and progression of diabetic complications. The receptor for AGE (RAGE) is the ligand-binding site of AGE that initiates and accelerates the atherosclerotic process. Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic factor that has been proposed as a biological marker for prognostic assessment, monitoring of microvascular and macrovascular complications in diabetes. The purpose of this study is to investigate the effects of aminoguanidine on RAGE and PAI-1 expression levels in the liver of streptozotocin-induced diabetic rats.
 Methods: Diabetes was induced in rats by intraperitoneal injection of streptozocin (STZ, 50 mg/kg). On day 3, diabetic rats were administered 50, 100, and 200 mg/kg/day of aminoguanidine. The expression of PAI-1 and RAGE in the liver tissue was evaluated using real-time PCR.
 Results: PAI-1 and RAGE gene expression levels were higher in the liver of the diabetic rats compared to the control group. Aminoguanidine at 50, 100, and 200 mg/kg decreased PAI-1 and RAGE gene expression in the liver (p<0.001 at all doses). However, these genes were downregulated only at a dose of 200 mg/kg in healthy rats (p<0.0001). In addition, hepatic AGE protein levels were significantly decreased following treatment of the diabetic rats with aminoguanidine (p<0.001). There was also a significant correlation between AGE protein concentration and the expression of PAI-1 and RAGE.
 Conclusion: In summary, the data of the present study suggest that aminoguanidine reduced the expression of PAI-1 and RAGE in the liver of the diabetic rats.

Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and other thrombophilia genes in patients with acute pulmonary embolism

Abstract Background Venous thromboembolism (VTE) is a serious threat to life and health, commonly known as the silent killer. Recent study has found that VTE is a polygenetic disease and more than 60% of deep vein thrombosis risk is influenced by genetic factors [1]. PAI-1 is a serine protease with negative feedback to fibrinolysis, activating and inhibiting coagulation [2]. The aim of this study was to elucidate the clinical impact of the PAI-1 4G/5G polymorphism and other thrombophilia in patients with acute PE. Methods A total of 58 subjects with acute PE and 60 healthy controls, were recruited in Institute of Cardiology. The accuracy of the RT-PCR method for detecting F5 G1691A (FVL) and PAI-1 4G/5G polymorphisms was evaluated by using sequencing method as the gold standard. Moreover, the association of the PAI-1 4G/5G polymorphism with susceptibility, treatment efficacy and recurrence status were explored. Eventually, we evaluated the association with inherited thrombophilia genes, such as the coagulation Factor V Leiden, prothrombin G20210A, FGB-455 G/A and methylenetetrahydrofolate reductase C677T and 1298 A/C. Results It was noted that the vast majority of patients with acute PE (87.9%) present polymorphism in the PAI-1 gene (29.3% homozygous (4G/4G) and 58.6% heterozygous (5G/4G)). Eleven patients out of 58 (19% of patients) showed factor V Leiden mutation and 19 patients out of 58 (32,7% of patients) showed mutation in FGB-455 G/A (2 homozygotes); MTHFR C677T gene mutation was found in 55,2%, while prothrombin 20210A gene mutation was presented in 6 patients (10.3% of patients). Nine patients (15,5% of patients) presented with chronic complication of VTE and 38.7% of patients showed recurrent pulmonary embolism. More than a half of patients (51.9%) had multiple gene mutation and only one presented with mutations in three studied genes. It showed a significant difference in the occurrence of other thromboses in the body and significant increase in the recurrence of pulmonary embolism and residual complications in these patients. It was also observed that individuals with the 4G/5G genotype had lower neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) than the 5G/5G genotype. Furthermore, it was underlined that the patients with the 5G/5G genotype were more likely to achieve complete recanalization compared to the 4G/4G genotype. Individuals carrying the 5G/5G genotype were more likely to develop a recurrence-free status as compared to those with the 4G/4G or 4G/5G genotypes. PAI-1 antigen levels in the VTE group were significantly higher than those in the HC group. Conclusion The PAI-1 4G/5G polymorphism has potential value in assessing the prognosis of patients with VTE. This study has laid the foundation for the application of PAI-1 4G/5G polymorphism in the personalized management and monitoring of patients with VTE. According to this study results PAI-1 4G/5G polymorphism could be included in laboratory testing panel of thrombophilia.

Endothelial dysfunction, thrombophilia, and nailfold capillaroscopic features in livedoid vasculopathy

BackgroundLivedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease. ObjectivesThis study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology. MethodsThis case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients. ResultsPlasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05–2.79] ng/ml vs. 1.89 [1.43–2.33] ng/ml, p = 0.007; 1.15 [0.88–1.4] ng/ml vs. 0.76 [0.56–0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26–18.26] vs. 19.80 % [16.47–24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-β2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %). ConclusionsIn conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.

Suppression of TGFβ-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38-NF-kB Pathway in Carcinoma Cells.

Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFβ-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFβ and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFβ-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFβ activities. In addition, SC-1 inhibits TGFβ-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.

PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity.

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

Acute myocardial infarction and pulmonary embolism in a young serviceman with a mutation of the plasminogen activator inhibitor gene type 1

The clinical case of acute myocardial infarction and pulmonary embolism in a young soldier with the first occurred protracted attack of angina. The survey found the link between these conditions and gene mutation of type 1 plasminogen activator inhibitor that plays a key role in fibrinolysis by inhibiting the formation of plasmin and leading to slowdown in fibrinolysis processes and a longer-term persistence of blood clot. It is proven that homozygous 4G/4G mutation found in the patient results in the development of arterial and venous thrombosis at a young age and is associated with a tendency to relapse. It clearly shows that hereditary thrombophilia is characterized by the absence of obvious provocative factor and single universal diagnostic algorithm; the diagnosis is based on the comprehensive evaluation of laboratory data.

Influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene in acute unprovoked deep vein thrombosis and residual vein thrombosis

BackgroundPlasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of plasminogen activator, but the role of the PAI-1 4G/5G polymorphism in deep vein thrombosis (DVT) has been contradictory. In this study, we investigated the distribution of the PAI-1 4G/5G genotype in Chinese patients with DVT compared with healthy controls and the association between the PAI-1 4G/5G genotype and the persistence of residual venous occlusion (RVO) after different treatments. MethodsThe PAI-1 4G/5G genotype was determined by fluorescence in situ hybridization in 108 patients with unprovoked DVT and 108 healthy controls. The patients with DVT were treated with catheter-based therapy or anticoagulation only. RVO was assessed by duplex sonography during the follow-up. ResultsThirty-two patients (29.6%) were homozygous for 4G (4G/4G), 62 patients (57.4%) were heterozygous for 4G/5G, and 14 patients (13%) were homozygous for 5G (5G/5G). No significant difference in genotype frequency was found between patients with DVT and controls. A total of 86 patients completed follow-up of ultrasound examination with a mean follow-up of 13.4 ±7.2 months. The results of patients with RVO were significantly different between homozygous 4G carriers (76.9%), heterozygous 4G/5G (58.3%), and homozygous carriers of 5G (33.3%) (P <.05) at the end of follow-up. Catheter-based therapy showed a better result in patients who were noncarriers of 4G (P = .045). ConclusionsThe PAI-1 4G/5G genotype was not a relevant predictor for DVT in Chinese patients, but is a risk factor for persistent RVO after idiopathic DVT.

Association of SNPs in the PAI1 Gene with Disease Recurrence and Clinical Outcome in Bladder Cancer.

Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Sequencing analyses identified two clinically relevant 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

Abstract TP222: Aging-associated Medin Induces Human Brain Microvascular Endothelial Cell Pro-inflammatory And Pro-thrombotic Activation Partly Via NFκB

Background: Vascular aging is characterized by endothelial dysfunction and proinflammatory &amp; prothrombotic changes. It is responsible for aging-associated pathologies including stroke, vascular dementia (VaD) and Alzheimer’s disease (AD). The underlying mechanisms of vascular aging are poorly understood. Medin is an amyloidogenic protein that accumulates in aging vasculature, is associated with VaD and AD, and is a candidate mediator of vascular aging through unknown mechanisms. Our aim is to test the hypothesis that medin induces proinflammatory and prothrombotic changes in human brain microvascular endothelial cells (HBMVECs) through nuclear factor kappa B (NFκB). Methods: HBMVECs were exposed to vehicle, recombinant medin (5 μM, a physiologically relevant dose) without or with RO106-9920 (a small molecule selective NFκB inhibitor, 10 μM) or RO106-9920 alone for 20 hours (N=3-17/treatment). Cell lysates were measured for gene expression of inflammatory cytokines/chemokines (IL-8, IL-6, ICAM-1 and VCAM-1) and thrombotic factors (thrombomodulin (TM), a transmembrane glycoprotein and potent inhibitor of coagulation, plasminogen activator inhibitor-1 (PAI-1) which promotes thrombosis and tissue factor (TF) which initiates the coagulation cascade), using real time PCR. Results: See Figure. Medin increased gene expression of IL-8, IL-6, ICAM-1, VCAM-1 and PAI-1, reduced TM with no change in TF. Co-treatment of medin with RO106-9920 attenuated the increases in IL-8, IL-6, ICAM-1, VCAM-1 and the reduction in TM, with no change in PAI-1. Conclusions: Medin caused increased pro-inflammatory gene expression in HBMVECs. It also caused reduced TM and increased PAI-1 gene expression, signifying prothrombotic activation. Co-treatment with NFκB inhibitor prevented medin’s proinflammatory effect, and effect on TM, but not PAI-1. The effect of inducing endothelial cell activation supports medin as a potential novel target to treat vascular aging.

Sneddon syndrome: A rare diagnosis

The study objective is to demonstrate a rare cause of recurrent acute cerebrovascular diseases in a young patient – Sneddon syndrome. The patient revealed gene polymorphism: homozygous 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene, C807T in the glycoprotein I gene (GPIa), T1565C in the glycoprotein III gene (GPIIIa), G1639A in the vitamin K epoxide reductase gene (VKORC1), increased homocysteine, which were risk factors for thrombosis.

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

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

Family-based analysis of -675 4G/5G polymorphism in the PAI-1 gene of polycystic ovary syndrome in Chinese population

Previous studies have shown that 4G/5G polymorphism in promoter region of plasminogen activator inhibitor-1 (PAI-1) gene can affect insulin sensitivity by elevating the level and activity of plasma PAI-1. In order to elucidate the relationship between the polymorphism of PAI-1 gene and polycystic ovary syndrome (PCOS), we used transmission disequilibrium test (TDT) to study the family of PCOS. Eight hundred and fifty-five participants consisting of 285 trios (mother, father and offspring with PCOS) were recruited at the Center of Reproductive Medicine, Shandong University from July 2007 to August 2014. 4G/5G polymorphism of PAI-1 gene was genotyped using direct sequencing protocol and TDT was used to analyse the association between PAI-1 gene and PCOS. Though the 5G allele in PAI-1 gene was overtransmitted in families, no statistical significance existed and there was no association between PAI-1 gene and PCOS, indicating that PAI-1 gene was unlikely to play a major role in the aetiology of PCOS in Chinese population. Impact Statement What is already known on this subject? Some studies have shown that 4G/5G polymorphism in promoter region of plasminogen activator inhibitor-1 (PAI-1) gene can affect insulin sensitivity by elevating the level and activity of plasma PAI-1, participating in the formation of insulin resistance (IR). What do the results of this study add? Though the 5G allele in PAI-1 gene was overtransmitted in families, no statistical significance existed and there was no association between PAI-1 gene and polycystic ovary syndrome (PCOS). What are the implications of these findings for clinical practice and/or further research? PAI-1 gene was unlikely to play a major role in the aetiology of PCOS.

Plasminogen activator inhibitor-1 level associated with the components of metabolic syndrome in a 4G/5G polymorphism dependent manner

Background and Aims : The elevated level of plasminogen activator inhibitor-1 (PAI-1) in obese subjects with metabolic syndrome and in patients with type 2 diabetes is well established. A common 4G/5G single guanine insertion/deletion polymorphism in the promoter region of the PAI-1 gene is of functional importance in regulating PAI-1 expression. We aimed to study the potential different correlations of carbohydrate and lipid parameters and plasma PAI-1 levels in the 4G and 5G carriers in obese and lean subjects.

Clinical case of thrombosis in a newborn child with congenital heart disease against the background of hereditary thrombophilia

Introduction. The problem of neonatal thrombosis is becoming increasingly urgent in clinical practice due to its importance in the development of a complicated course of the neonatal period in children with hereditary and acquired thrombogenic risk factors. The aim of the investigation is to present a clinical case of multiple thromboses in a premature newborn infant with congenital heart disease on the background of multigenic thrombophilia, complicated by neonatal sepsis. Materials and methods. Materials for the investigation were the primary medical records: history of the newborn, medical history of the patient-newborn child with the established diagnosis of great-vessel thrombosis, with the congenital heart disease and the presence of genetic thrombophilia, who was under observation for 2 months. The findings of objective, laboratory (clinical blood tests, investigation of hemostasis parameters, homocysteine concentration, molecular-genetic study of hemostasis enzymes genes, folate cycle enzymes genes) and instrumental (CT angiography, ultrasonic examination of abdominal cavity and retroperitoneal organs, ECHO cardiography, ultrasonic Dopplerography) research methods were evaluated. Results and Discussion. In the clinical observation under consideration, there was a burdened molecular genetic background consisting of carriage of plasminogen activator inhibitor gene polymorphisms and folate cycle enzyme genes: MTHFR 677 – C/T, MTHFR 2756 – A/G, MTRR 66 – G/G, and hyperhomocysteinemia were the factors responsible for multiple thrombosis in a patient born with critical congenital heart disease (CHD), contributed to generalization of the infection process with the development of multiple organ failure, and exacerbated the postoperative period after correction of heart disease. Conclusion. The clinical case demonstrates the development of multiple thrombosis and septic process in a child born with CHD. The results of molecular genetic study proved the presence of hereditary thrombophilia in the child, which was a predictor of thrombosis development and probably a risk factor aggravating the severity of generalized infectious process, which complicated pre- and postoperative periods of the main disease, CHD.

The efficacy of salivary Histatin-1 protein in wound closure of nicotine treated human periodontal ligament fibroblast cells – In vitro study

ObjectivesThe aims of this study were to investigate the efficacy of Histatin-1 in wound closure as well as effects on gene expression of nicotine-treated human Periodontal Ligament Fibroblast cells (HPDL) in vitro. DesignHPDL grown in 2.5% culture medium treated with 10 ng/ml Histatin − 1 in the presence/absence of 0.5 µM nicotine were subjected to wound assay and migration was studied at 0 h, 6 h, 12 h and 24 h. Cells grown in 2.5% medium served as control. Cell migration was studied by wound gap and transwell migration assays. The effect of Histatin-1 on expression of matrix metalloproteinase 8 (MMP-8), insulin-like growth factor 1 (IGF-1), transforming growth factor beta (TGF-β), collagen type I (COL1) and plasminogen activator inhibitor 1 (PAI-1) were studied. ResultsHistatin-1 treatment significantly decreased percentage wound gap at 12 h (62.96 ± 3.22 vs 79.23 ± 1.73; p < 0.05) and at 24 h (38.78 ± 7.59 vs 75.21 ± 4.94; p < 0.001) compared with controls. In nicotine+Histatin-1 treated cells, wound gap decreased to 70.2 ± 2.9% (p < 0.01) at 24 h compared to nicotine alone in which 82 ± 1.64% of wound gap was retained. Transwell migration assays showed significant migration of HPDL with Histatin-1 (p < 0.05). Gene expression demonstrated significant upregulation for IGF-1, TGF β, COL1 and PAI-1 with Histatin-1. ConclusionHistatin-1 significantly mitigated the effect of nicotine in wound healing assay involving HPDL fibroblast cells at 24 h. Histatin-1 aided wound closure is attributed to the upregulation of IGF-1, TGF β, COL1, and PAI-1 genes.

The Role of 4G Allele in Plasminogen Activator Inhibitor-1 (rs1799889) Gene as Biomarker for Thrombophilic States among Patients with Type 2 Diabetes

The Role of 4G Allele in Plasminogen Activator Inhibitor-1 (rs1799889) Gene as Biomarker for Thrombophilic States among Patients with Type 2 Diabetes

Genetic variations of renin-angiotensin and fibrinolytic systems and susceptibility to coronary artery disease: a population genetics perspective.

Genetic predisposition is an important risk factor in coronary artery disease (CAD).This study was conducted to determine the polymorphism frequencies of the plasminogen activator inhibitor-1(PAI-1) gene 4G/5G, angiotensin-converting enzyme (ACE) gene I/D, and angiotensin II type 1 receptor (AT1) gene A1166C genotypes and to examine the role of these polymorphisms in CAD. Genomic DNAs obtained from 260 subjects (130 CAD patients and 130 control) were used in the study. ACE I/D and PAI-1 4G/5G polymorphism genotypes were determined using polymerase chain reaction (PCR) and electrophoresis. AT-1 A1166C polymorphism was determined using the PCR, restriction fragment length polymorphism (RFLP) and electrophoresis. The products amplified from AT1 gene by PCR were cut with HindIII restriction endonuclease and then analyzed by 2% agarose gel electrophoresis. The results were statistically analyzed with the chi-square test, Mann-Whitney U test, and independent two-sample t-test. Allele frequencies showed statistically significant differences between the patient and control groups. There was no statistically significant difference in ACEI/D genotype frequencies between the twogroups. Likewise, no statistically significant difference was found in the AT1 A1166C genotype frequencies; however, a statistically significant difference was found in allele frequencies. The PAI-1 4G/5G genotype frequency was significantly higher in the patient group. While there is a relationship between of PAI-1 gene 4G/5G polymorphism and CAD, ACE gene I/D and AT1 gene A1166C polymorphisms are not related. PAI-1 gene homozygous genotypes may be considered as a prognostic marker for CAD patients.

Features of plasminogen activator inhibitor-1 synthesis by local fat depots of different localization in cardiovascular diseases

Aim. To determine the features of expression and secretion of plasminogen activator inhibitor-1 (PAI-1) by subcutaneous, epicardial and perivascular adipocytes depending on the complexity of coronary artery disease (CAD).Material and methods. The study included 86 patients with CAD, including 35 with moderate atherosclerotic lesions of the coronary arteries (CA) (SYNTAX Score ≤22), 22 with severe (SYNTAX Score of 23-31 pints), 29 with extremely severe (SYNTAX Score ≥32). As a comparison group, 52 patients with heart defects were examined. During an elective surgical intervention, adipose tissue (AT) samples were obtained for subsequent cultivation and determination of PAI-1 gene expression and PAI-1 secretion in AT supernatants of various localizations. Statistical analysis was performed using Statistica 10.0.Results. In CAD, PAI-1 production in all three types of AT and plasma PAI-1 concentration were increased compared with patients with heart defects. Epicardial AT (EAT) in CAD was characterized by the maximum levels of expression and secretion of PAI-1 relative to patients with heart defects and subcutaneous and perivascular (PVAT) fat depots. Moderate coronary involvement (adipose tissue &lt;22) is characterized by the lowest expression and secretion of PAI-1 in all types of AT and plasma concentration of PAI-1. Direct correlations of PAI-1 expression and secretion in EAT and PVAT and plasma PAI-1 level with its secretion in EAT in patients with CAD and heart defects were revealed. A direct correlation between the plasma level of PAI-1 and its secretion in PVAT was found only in CAD.Conclusion. In CAD, there is not only an increase in the plasma PAI-1 level, but also an increase in the expression of PAI-1 gene and the secretion of PAI-1 in all three types of AT compared with patients with heart defects. PAI-1 expression and secretion in EAT, PAI-1 plasma level, and age are predictors of severe/extremely severe coronary involvement in CAD.

Features of plasminogen activator inhibitor-1 synthesis by local fat depots of different localization in cardiovascular diseases

Aim. To determine the features of expression and secretion of plasminogen activator inhibitor-1 (PAI-1) by subcutaneous, epicardial and perivascular adipocytes depending on the complexity of coronary artery disease (CAD).Material and methods. The study included 86 patients with CAD, including 35 with moderate atherosclerotic lesions of the coronary arteries (CA) (SYNTAX Score ≤22), 22 with severe (SYNTAX Score of 23-31 pints), 29 with extremely severe (SYNTAX Score ≥32). As a comparison group, 52 patients with heart defects were examined. During an elective surgical intervention, adipose tissue (AT) samples were obtained for subsequent cultivation and determination of PAI-1 gene expression and PAI-1 secretion in AT supernatants of various localizations. Statistical analysis was performed using Statistica 10.0.Results. In CAD, PAI-1 production in all three types of AT and plasma PAI-1 concentration were increased compared with patients with heart defects. Epicardial AT (EAT) in CAD was characterized by the maximum levels of expression and secretion of PAI-1 relative to patients with heart defects and subcutaneous and perivascular (PVAT) fat depots. Moderate coronary involvement (adipose tissue &lt;22) is characterized by the lowest expression and secretion of PAI-1 in all types of AT and plasma concentration of PAI-1. Direct correlations of PAI-1 expression and secretion in EAT and PVAT and plasma PAI-1 level with its secretion in EAT in patients with CAD and heart defects were revealed. A direct correlation between the plasma level of PAI-1 and its secretion in PVAT was found only in CAD.Conclusion. In CAD, there is not only an increase in the plasma PAI-1 level, but also an increase in the expression of PAI-1 gene and the secretion of PAI-1 in all three types of AT compared with patients with heart defects. PAI-1 expression and secretion in EAT, PAI-1 plasma level, and age are predictors of severe/extremely severe coronary involvement in CAD.

Plasminogen Activator Inhibitor-1 Polymorphisms and Risk of Coronary Artery Disease: Evidence From Meta-Analysis and Trial Sequential Analysis.

A systematic review and meta-analysis were conducted to find out if there was association between Plasminogen Activator Inhibitor-1 (PAI-1) gene polymorphisms (- 844 G > A and - 675 4G > 5G) and susceptibility to coronary artery disease (CAD). Search of electronic databases was performed and the pooled odds ratio (OR) and 95% confidence interval (CI) were exerted to evaluate the pooled association between the single-nucleotide polymorphisms (SNPs) and risk of CAD. For - 675 4G > 5G SNP, dominant (OR = 0.90), recessive (OR = 0.90), allelic (OR = 0.91), homozygous (OR = 0.84), and heterozygous (OR = 0.96) models were significantly associated with decreased risk of CAD. Moreover, all five genetic models were associated significantly with decreased CAD risk in the Causation and Arab populations. The results in Asians were marginally significant in recessive, allelic, and homozygote models. The male gender was found to be a risk factor in individuals with PAI-1 4G > 5G SNP in the dominant model (OR = 0.89), recessive model (OR = 0.91), allelic model (OR = 0.92), homozygous model (OR = 0.86), and heterozygous model (OR = 0.91). The results of pooled ORs for overall populations and subgroup analysis by ethnicity reject any association between PAI-1 gene - 844 G > A polymorphism and CAD risk under all genetic comparisons. The results of this meta-analysis indicated that PAI-1 4G > 5G SNP was associated with decreased risk of CAD in the overall population as well as in the Asians, Caucasians, and Arab populations. However, the PAI-1 gene - 844 G > A polymorphism had no significant association with susceptibility to CAD.