Plasminogen Activator Inhibitor Type Research Articles

Mitogen-activated protein kinase inhibitors reduce the nuclear accumulation of phosphorylated Smads by inhibiting Imp 7 or Imp 8 in HepG2 cells.

The transforming growth factor (TGF)-β/Smad signaling pathway is involved in hepatocellular carcinoma development. Smad2 and Smad3 are phosphorylated following TGF-β1 stimulation and subsequently oligomerize with Smad4 to form the Smad2/3/4 complex, which translocates into the nucleus and regulates target genes, including plasminogen activator inhibitor type 1 (PAI1). Importin (Imp)7 and Imp8 are responsible for transporting phosphorylated (p)Smad2/3 and Smad4 into the nucleus. In our previous study, it was demonstrated that mitogen-activated protein kinase (MAPK) inhibitors, including inhibitors of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 could inhibit the transcription of PAI1, but ERK inhibitor had no significant effect on the phosphorylation of Smad2/3, and the formation of Smad2/3/4 complexes, which was different from the effect of JNK or p38 inhibitor. We hypothesized that MAPK inhibitors, particularly ERK inhibitor, reduced the transport of Smads into the nucleus by affecting Imp7 and Imp8. To confirm this hypothesis, HepG2 cells were incubated with different MAPK inhibitors for 5 h and subsequently stimulated with TGF-β1 for 1 h. Next, the intracellular locations of Smads (pSmad2C, pSmad2L, pSmad3C, pSmad3L and Smad4) and Imp7/8 were detected using immunofluorescence staining assays, and the expression of Imp7/8 was investigated using immunoblotting. It was revealed that JNK or p38 inhibitor decreased the phosphorylation of Smad2C, Smad2L and Smad3L, and affected their nuclear accumulation. Although only inhibiting the phosphorylation of Smad2C, ERK inhibitor affected the nuclear accumulation of pSmad2C, pSmad2L, pSmad3C and pSmad3L. The three MAPK inhibitors attenuated the nuclear distribution of Smad4, and the expression and nuclear accumulation of Imp7. ERK and JNK inhibitors attenuated the expression and nuclear accumulation of Imp8. Thus, the results of the present study suggest that MAPK inhibitors, particularly ERK inhibitor, modulate the nuclear accumulation of Smads via the inhibition of Imp 7/8.

Identification of Basic Fibroblast Growth Factor as the Dominant Protector of Laminar Shear Medium from the Modified Shear Device in Tumor Necrosis Factor-α Induced Endothelial Dysfunction.

Background and Aims: Endothelial dysfunction is a hallmark of cardiovascular diseases. The straight region of an artery is protected from atherosclerosis via its laminar blood flow and high shear stress. This study investigated the cytoprotective effects of a new laminar shear medium (LSM) derived from a modified cone-and-plate shear device and identified basic fibroblast growth factor (bFGF) secreted by human aortic endothelial cells (HAECs) as the dominant protective factor in the LSM.Methods: Based on a modified cone-and-plate shear device system, HAECs were exposed to laminar shear (15 dynes/cm2) and static control for 24 h to produce a new supernatant LSM and static medium (SM). Evaluation of the protective effects of LSM and SM on endothelial dysfunction induced by tumor necrosis factor (TNF)-α (10 ng/mL), which leads to production of reactive oxygen species (ROS), inflammatory monocyte adhesion, and tissue factor activity. ROS induction-, inflammation-, and thrombosis-related genes and protein expression were evaluated by quantitative-PCR and western blotting. To identify the cytokines that played a key role in the cytoprotective action of the LSM, we used cytokine antibody arrays, selected an abundant marker cytokine, bFGF, and validated the different cytoprotective effects of recombinant bFGF (rbFGF) and neutralization by monoclonal antibody (rbFGF+Ab) co-treatment. Aortic and lung tissues from different groups of C57BL/6J mice were examined by immunohistochemistry. SB203580 (specific inhibitor of p38) and BIX02189 (specific inhibitor of MEK5) were used to identify bFGF as the main cytoprotective factor acting via p38/MAPK and MEK5-KLF2 pathways.Results: Compared with traditional LSM, the new LSM not only significantly decreased TNF-α-induced intracellular adhesion molecule 1 and plasminogen activator inhibitor type 1 gene expression, but also significantly increased heme oxygenase 1 gene expression. The new LSM and bFGF attenuated TNF-α-induced ROS induction, inflammation, and tissue factor activity and inhibited the inflammatory- and thrombosis-related gene/protein overexpression both in vitro and in vivo. Mechanistically, the cytoprotective action of bFGF was mediated via the p38/MAPK and MEK5-KLF2 pathways.Conclusion: bFGF was identified as the critical factor mediating the cytoprotective effects of LSM derived from the modified laminar shear system.

D-dimer predicts pulmonary embolism after low-risk spine surgery.

Introduction Pulmonary embolism (PE) is a risk of mortality following spine surgery. Many studies have demonstrated that deep venous thrombosis (DVT) may affect and actually advance to PE, but few studies have shown how venous thromboembolism (VTE), including PE and DVT, affect blood markers after spine surgery. In this study, we examined changes in blood markers with PE or DVT after low-risk spine surgery, namely cervical laminoplasty or lumbar laminectomy. Methods Seventy-two spine surgery patients were studied. A 16-row multidetector computed tomography was performed before and 3 d after the surgery. Patients with a history of cerebral vascular accident or arterial thrombotic episode or pre-surgical asymptomatic PE or DVT were excluded. Plasma levels of soluble fibrin monomer complex, D-dimer, plasminogen activator inhibitor type-1 (PAI-1), and white blood cell and platelet counts were measured preoperatively and postoperatively at days 1, 3, and 7. Results No patient developed symptomatic post-surgical VTE. Six patients with asymptomatic PE and six with asymptomatic DVT were detected post-surgery, including one patient with both. D-dimer postoperatively at days 3 and 7 was significantly higher in the post-op PE group than in the no-PE group. PAI-1 preoperatively was significantly higher in the DVT and VTE groups than in the no-DVT and no-VTE groups. Conclusions Elevated D-dimer at postoperative days 3 and 7 is a predictive factor for the early diagnosis of PE after spine surgery. Moreover, elevated PAI-1 preoperatively is a predictive factor for the early diagnosis of DVT and VTE. Consequently, PE may occur through a pathway other than DVT.

APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats.

APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.

PECULIARITIES OF NEPHROPROTECTIVE EFFECT OF SULODEXIDE IN PATIENTS WITH DIABETIC NEPHROPATHY

Introduction. Monocyte chemoattractant protein type 1 (MCP-1) and plasminogen activator inhibitor type 1 (PAI-1) play a key role in inflammation, fibrosis and progression of renal dysfunction. Sulodexide advantages in vascular pathology treatment were proved by clinical trials, however, its efficiency in diabetic nephropathy (DN) was investigated insufficiently.
 The aim of the present work – to study the influence of sulodexide on clinical and laboratory parametres, MCP-1 and PAI-1 levels in blood plasma of patients with DN.
 Materials and methods. 76 type 2 diabetic patients with different stages of DN were observed. 44 patients received basic therapy with anti-diabetic drugs and ACE- inhibitors, 32 patients in addition to basic therapy were treated with sulodexide in a daily dose 600 LU. Concentrations of MCP-1 and PAI-1 in blood plasma were determined using immunoassay kits.
 Results. In patients with DN when compared with healthy controls MCP-1 and RAI-1 levels in blood plasma significantly increased already at initial stages of the disease. Such changes may promote a development of inflammatory and fibrotic processes in kidneys. Progression of the disease was accompanied by more essential growth of MCP-1 and RAI-1 in DN patients with expressed clinical manifestations of kidney injury. Sulodexide treatment in patients with DN resulted in essential decrease of inflammatory and fibrotic markers and had positive effect on urinary protein excretion.
 Conclusions. Glicosaminoglycans, in particular, sulodexide, is effective in complex treatment of patients with DN.

Prognostic value of urokinase plasminogen activator system in non-small cell lung cancer: A systematic review and meta-analysis.

Current relevant research suggests there are significant differences between the expression of the urokinase plasminogen activator (uPA) system in cancer tissues and in normal tissues. However, the potential effectiveness of the uPA system as a prognostic biomarker of non-small cell lung cancer (NSCLC) remains unclear. In the present study, a systematic review and meta-analysis were performed to evaluate the relevance of the uPA system in the prognosis of patients with NSCLC. Using the PubMed, EMBASE, Web of Science and Cochrane Library databases, data from relevant academic journal articles were extracted and subjected to analysis. Associations between expression profiles pertaining to the uPA system and the overall survival (OS) of patients with NSCLC were analyzed. The study incorporated data from 11 independent journal articles and these reports included a total of 937 patients with NSCLC. The meta-analysis results revealed that increased expression of urokinase plasminogen activator (uPA) and PA inhibitor type 1 (PAI-1) exhibited no significant association with poor OS [hazard ratio (HR)-uPA=1.07 (0.87-1.31), P=0.53; HR-PAI-1=1.02 (0.63-1.65), P=0.94]. Similarly, reduced expression of PAI type 2 (PAI-2) did not significantly correlate with poor OS [HR-PAI-2=1.58 (0.64-3.90); P=0.32]. Notably, however, a significant association was observed between increased expression levels of uPA receptor (uPAR) and poor OS for NSCLC [HR-uPAR=1.50 (1.04-2.15); P=0.03]. Therefore, the expression of uPAR in the uPA system of patients with NSCLC could be used as a novel clinical biomarker to evaluate the prognosis of NSCLC. The utilization of this biomarker may provide a platform for the further development of targeted drugs for the treatment of NSCLC.

Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases.

Plasminogen activator inhibitor type 1 (PAI-1) is the main physiologic inhibitor of fibrinolysis. However, it is also involved in many physiological processes such as extracellular matrix (ECM) proteolysis and remodeling, cell adhesion, motility, and apoptosis, angiogenesis, etc. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies (atherosclerosis, tissue fibrosis, cancer metastasis, pregnancy related complications, etc). As a component of an early cellular response to injury, PAI-1 reacts with membrane surface proteins and participates in the initiation of intracellular signaling, specifically cytoskeletal reorganization and motility. Complexity of ECM homeostasis resides in varying relation of the plasminogen system components and other matrix constituents. Inflammatory mediators (transforming growth factor-β and interferon-γ) and hormones (angiotensin II) are in the close interdependent relation with PAI-1. Also, special attention is devoted to the role of increased PAI-1 concentrations due to the common 4G/5G polymorphism. Some of the novel mechanisms of ECM modification consider PAI-1 dependent stabilization of urokinase mediated cell adhesion, control of the vascular endothelial cadherin trafficking and interaction with endothelial cells proteasome, its relation to matrix metalloproteinase 2 and osteopontin, and oxidative inhibition by myeloperoxidase. Targeting and/or alteration of PAI-1 functions might bring benefit to the future therapeutic approaches in diseases where ECM undergoes substantial remodeling.

Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury.

More than 80% of traumatic brain injury (TBI) patients suffer from mild TBI (mTBI). However, even mTBI carries the risk of late pituitary dysfunction. A predictive biomarker at the time of injury that could identify patients who subsequently may develop permanent pituitary dysfunction would help to direct patients toward endocrine care. We enrolled 508 TBI patients (406 with mTBI) into our study. Blood samples were collected for identification of predictive biomarkers of late pituitary dysfunction at the time of admission. Follow-up blood samples were collected between 6 and 12 months after the TBI and were evaluated for pituitary function. Of the 406 mTBI patients, 76 were available for follow-up. Pre-existing mild pituitary dysfunction was found for 15 patients based on hormone levels at the time of injury. Of the remaining 61 patients, 10 have shown deficiency in at least one pituitary hormone: 4 had growth hormone deficiency, 3 gonadotropin, 2 thyrotropin, and 1 patient combined gonadotropin and thyrotropin deficiency. Hence, newly developed pituitary hormone deficiency was found in 16% of mTBI patients. Neither the cause of mTBI nor its complications were predictive of late pituitary dysfunction. Of the hemostasis parameters studied, lower plasminogen activator inhibitor type 1 (PAI-1) level at the time of injury was found to be predictive for the development of late pituitary dysfunction; sensitivity, specificity, and positive and negative predictive values were 80%, 67%, 32%, and 94%, respectively. Even mTBI carries a substantial risk of endocrine consequences. Serum PAI-1 level at the time of TBI may serve as a predictive biomarker of late pituitary dysfunction in mTBI patients.

The Cytoskeletal Network Regulates Expression of the Profibrotic Genes PAI-1 and CTGF in Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are subject to changing hemodynamic stimuli that alter cytoskeletal dynamics, cellular architecture, and structure-associated signal transduction. Tensional stress, force application, and structural perturbations are sensed by VSMCs and impact the physiological as well as pathophysiological responses of the vasculature. Microtubule-targeting drugs provide useful tools to analyze cytoskeletal-associated signaling pathways and their linkages to pathological outcomes. Architecture-based controls on a subset of profibrotic genes commonly expressed in vascular disease are highlighted by their frequent induction in mechanically manipulated cells and with associated changes in cytoskeletal dynamics. VSMCs respond to biomechanical cues by activating several kinase cascades, leading to gene reprogramming. It is apparent that a significant fraction of the vast repertoire of signaling intermediates, moreover, are sequestered on the cytoskeletal framework in an "inactive state." Reorganization within these networks due to fluctuating mechanical forces could release these effectors from their cytoskeletal anchors, thus alleviating the "repressive state" resulting in downstream signaling. Indeed, recent findings indicate that microtubule disruption in VSMCs rapidly stimulates pp60c-src kinase activation and epidermal growth factor receptor (EGFR) transphosphorylation at Y845, a src kinase target residue. EGFR genetic deficiency, pharmacological inhibition of EGFR signaling, or adenoviral delivery of the kinase-deficient EGFRK721A construct effectively blocked colchicine-stimulated expression of two prominent vascular profibrotic genes, plasminogen activator inhibitor type-1 (PAI-1; SERPINE1) and connective tissue growth factor (CTGF; CCN2). Signaling intermediates involved in microtubule collapse-initiated PAI-1/CTGF induction in VSMCs include the MEK/ERK, Rho/ROCK, and SMAD2/3 pathways. This review highlights commonalities and differences in signaling events that facilitate expression of vascular disease-relevant genes initiated as a consequence of loss of microtubular integrity.

New insights into sinusoidal obstruction syndrome.

Entry criteria included patients who developed sinusoidal obstruction syndrome (SOS) at a single centre from January 2000 to December 2011. Patients who underwent haemopoietic stem cell transplantation or actinomicyn-based chemotherapy for nephroblastoma were selected. The study group comprised five patients with SOS who were compared with a control group of seven patients without SOS. To study the relationships between endothelial extracellular vesicles (EV) and plasminogen-activator inhibitor type 1(PAI-1) to assess their modification in the early phase of SOS. Consecutive blood samples were tested for cell-derived EV, PAI-1 and coagulation parameters. Any statistically significant correlation between all datasets was searched. Antithrombin level and platelet count were statistically significantly reduced in SOS patients, suggesting a consumption status. PAI-1:Ag and PAI-1:act showed an inverse relationship with platelet counts (coef. -0.034, SE = 0.016; P = 0.041 and -0.052, SE = 0.019; P = 0.011 respectively). During follow up, PAI-1:Ag was inversely related to EV CD144+ (coef. -0.261, SE = 0.094; P = 0.007) and antithrombin (coef -0.509, SE = 0.175; P = 0.005). PAI-1:act showed an inverse association with EV CD144+ (coef.-0.251, SE = 0.121; P = 0.043), EV CD31+/CD41+ (coef. -0.004, SE = 0.002; P = 0.026) and antithrombin (coef. -0.470, SE = 0.220; P = 0.038). EV generated by rupture of gap junctions (EV CD144+) were increased in SOS patients and also showed a change over time. This study demonstrates the existence of an ongoing procoagulant and hypofibrinolytic status in SOS, indicating a possible role for anticoagulant therapy. Moreover, these findings suggest a role for EV CD 144+, either alone or in combination with PAI-1, as a new biomarker for SOS.

MiR-30c may serve a role in endometriosis by targeting plasminogen activator inhibitor-1.

The present study aimed to investigate the role of miR-30c in endometriosis (EMs) and the underlying mechanism. The expression of miR-30c and plasminogen activator inhibitor type 1 (PAI-1) mRNA in EMs tissues was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the expression of PAI-1 protein was detected by western blot analysis. The proliferation, migration, invasion and adhesion of endometrial stromal cells (ESCs) in different groups transfected with miR-30c mimic or inhibitor were compared. It was demonstrated that miR-30c expression in ectopic and eutopic endometriosis tissues were significantly lower than in normal endometrial tissue. However, PAI-1 mRNA expression in ectopic and eutopic endometrial tissues was higher than in normal endometrial tissues. Furthermore, the expression of PAI-1 protein was higher in ectopic and eutopic endometrosis tissues than in normal tissues. RT-qPCR results indicated that miR-30c expression was significantly increased or decreased in ESCs following transfection of mimic or inhibitor of miR-30c, respectively. Overexpression of miR-30c repressed the expression of PAI-1 mRNA and protein, while inhibition of miR-30c upregulated the expression of PAI-1 in ESCs. In addition, the invasion, migration, proliferation and adhesion of ESCs was repressed following the overexpression of miR-30c, whereas they were promoted when miR-30c expression was downregulated. The results of the present study indicated that miR-30c serves an important role in the development and progression of EMs by regulating the expression of PAI-1.

N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes

ObjectiveWe previously demonstrated that diabetes exacerbates stroke-induced brain injury, and that this correlates with brain methylglyoxal (MG)-to-glutathione (GSH) status. Cerebral injury was reversed by N-acetylcysteine (NAC). Here we tested if the pro-thrombotic phenotype seen in the systemic circulation and brain during diabetes was associated with increased MG-glycation of proteins, and if NAC could reverse this. MethodsThe streptozotocin (STZ)-induced mouse model of type 1 diabetes was used. Thrombus formation in venules and arterioles (pial circulation) was determined by intravital videomicroscopy using the light-dye method. Circulating blood platelet-leukocyte aggregates (PLAs) were analyzed by flow cytometry 1 wk before other measurements. GSH and MG levels in platelets were measured by HPLC. MG-modified proteins, glutathione peroxidase-1 (GPx-1), and superoxide dismutase-1 (SOD1) levels were detected in platelets by western blot at 20 weeks. Proteins involved in coagulation were quantified by ELISA. NAC (2mM) was given in drinking water for 3 weeks before the terminal experiment. ResultsThrombus development was accelerated by diabetes in a time-dependent manner. % PLAs were significantly elevated by diabetes. Plasma activated plasminogen activator inhibitor type 1 levels were progressively increased with diabetes duration, with tail bleeding time reduced by 20 wks diabetes. Diabetes lowered platelet GSH levels, GPx-1 and SOD-1 expression. This was associated with higher MG levels, and increased MG-adduct formation in platelets. NAC treatment partly or completely reversed the effects of diabetes. ConclusionCollectively, these results show that the diabetic blood and brain become progressively more susceptible to platelet activation and thrombosis. NAC, given after the establishment of diabetes, may offer protection against the risk for stroke by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.

Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

BackgroundThe cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM).MethodsFifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross-over trial and...

Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases.

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Expression, Intracellular Localization, and Prognostic Value of Plasminogen Activator Inhibitor 1 and PAI-1 RNA-Binding Protein 1 in Primary and Recurrent Ovarian Cancer: A Study of the Tumor Bank Ovarian Cancer Network

Background: The plasminogen activator system plays a key role in ovarian cancer (OC) tumor progression. The plasminogen activator inhibitor type 1 (PAI-1) and the recently identified PAI-1 RNA binding protein 1 (PAI-RBP1) are primary regulators of plasminogen activation and thus are putative biomarkers for OC progression. Methods: One hundred fifty six OC patients were analyzed to identify the presence of PAI-1 and PAI-RBP1 and subsequently correlated to clinicopathological parameters. Primary cells obtained from OC patient samples were applied in fluorescence microscopy analysis for examination of PAI-1 and PAI-RBP1 distribution. Results: PAI-1 and PAI-RBP1 have been found to be predictive markers for OC patients' outcome. PAI-1 levels significantly correlated with volume of ascites, FIGO staging, and lymph node status. PAI-RBP1 expression significantly correlated with age at first diagnosis, histological tumor type, presence of distant metastasis (pM), and recurrence. PAI-1 showed a trend toward association and PAI-RBP1 was significantly associated with progression-free survival. Notably, PAI-1 protein in recurrent OC tissues was exclusively localized in the nucleus. Conclusion: This study has shown that a combination of PAI-1 and PAI-RBP1 may represent novel prognostic factor for OC. Prospective trials are needed.

Conditional Plasminogen Activator Inhibitor Type 1 Deletion in the Endothelial Compartment Has No Beneficial Effect on Radiation-Induced Whole-Lung Damage in Mice

To investigate whether the endothelial pool of plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of radiation-induced lung damage, as previously demonstrated in the intestine. Human lung microvascular endothelial cells were exposed to 10Gy irradiation so as to study their ability to acquire an "activated" phenotype. Mice in which the Cre-Lox strategy was used to produce PAI-1 deletion specifically in the endothelial compartment were exposed to 17Gy whole-thorax irradiation and followed up for 2, 13, and 23weeks after irradiation. Human lung microvascular endothelial cells had an activated phenotype after radiation exposure, overexpressed PAI-1, and underwent endothelial-to-mesenchymal transition. In mice, knockout of PAI-1 in the endothelium had no beneficial effect on radiation-induced lung damage and showed a tendency to worsen acute lesions. As opposed to the intestine, the endothelial pool of PAI-1 does not play a determinant role in the development of radiation-induced lung damage. The therapeutic value of PAI-1 inhibition in lung radiation injury may be associated with other types of cells.

МАРКЕРЫ ВОСПАЛЕНИЯ, ПОКАЗАТЕЛИ ГЕМОСТАЗА И СОСТОЯНИЕ ОРГАНОВ-МИШЕНЕЙ У МОЛОДЫХ ПАЦИЕНТОВ С РАЗЛИЧНЫМИ КОМПОНЕНТАМИ МЕТАБОЛИЧЕСКОГО СИНДРОМА

Введение. Согласно современным представлениям, инициирующим фактором для запуска каскада метаболических нарушений при артериальной гипертензии (АГ) и абдоминальном ожирении (АО) является инсулинорезистентность. Активация локального и системного воспалительного ответа, а также протромботические изменения при АГ и АО являются основой для органных поражений, прогрессирования атеросклеротического процесса и развития осложнений. Цель исследования. Изучение взаимосвязи между маркерами воспалительного ответа, показателями гемостаза и состоянием органов-мишеней у молодых пациентов с различными компонентами метаболического синдрома. Материалы и методы. Проведена комплексная оценка взаимосвязи уровней адипокинов, цитокинов и показателей гемостаза с состоянием органов-мишеней у 251 пациента в возрасте 18–44 лет: 1 группа — 35 пациентов с изолированной АГ; 2 группа — 76 пациентов с изолированным АО; 3 группа — 60 пациентов с сочетанием АГ и АО; 4 группа — 80 практически здоровых волонтеров. Результаты. У больных с комбинацией АГ и АО выявлено повышение лептина и интерлейкина-6, снижение адипонектина и протромботические изменения гемостаза по сравнению с пациентами с изолированными АГ, АО и практически здоровыми. В группе больных с комбинацией АГ и АО с бóльшей частотой обнаруживались гипертрофия левого желудочка и увеличение комплекса интима-медиа сонных артерий по сравнению с пациентами, имевшими только АГ и только АО. Обнаружены положительные линейные корреляции индекса массы миокарда левого желудочка с концентрацией интерлейкина-6 и толщины комплекса интима-медиа с уровнем интерлейкина-1β, отрицательная связь этих показателей с уровнями адипонектина и ингибитора активатора плазминогена 1 типа. Заключение. При сочетании АГ с АО в молодом возрасте чаще выявляется субклиническое поражение органов-мишеней; установлено более высокое содержание глюкозы, общего холестерина, холестерина липопротеинов низкой плотности, триглицеридов, лептина, интерлейкина-6, фибриногена, ингибитора активатора плазминогена 1 типа и ингибитора пути тканевого фактора по сравнению с пациентами с изолированной АГ и изолированным АО. Introduction. According to modern concepts insulin resistance is the initiating factor for triggering a cascade of metabolic disorders in hypertension (AH) and abdominal obesity (AO). Activation of local and systemic infl ammatory response as well as prothrombotic changes at AH and AO are the basis for organ’s lesions, progression of atherosclerotic process and complications development. The aim: to study the relationship between the markers of infl ammatory response, hemostatic parameters and target organs in young patients with diff erent components of metabolic syndrome. Materials and methods. Complex assessment of relationships between adipokines, cytokines, hemostatic parameters and status of target organs was done in 251 patients (18–44 years old): group 1–35 patients with isolated AH; group 2–76 patients with isolated AO; group 3–60 patients with combination of AH and AO; group 4–80 practically healthy volunteers. Results. In patients with combination of AH and AO we revealed increased values of leptin and interleukin-6, decreased values of adipokine and prothrombotic changes as compared to patients with isolated AH, isolated AO and with healthy people. Left ventricular hypertrophy and thickening of intima-media of carotid arteries were revealed more frequently in patients with combination of AH and AO. We found positive correlations between the left ventricular mass index and interleukin-6 content, thickening of intima-media complex and interleukin-1β concentration, negative correlation of these parameters with adiponectin level and plasminogen activator inhibitor type 1 content. Conclusion. The subclinical lesion of target organs is more often detected in young people with AH in combination with AO; higher levels of glucose, total cholesterol, low-density lipoprotein cholesterol, triglycerides, leptin, interleukin-6, fibrinogen, inhibitor of plasminogen activator type 1 and inhibitor of tissue factor were revealed as compared to patients with isolated AH and with isolated AO.

Anti-inflammatory effects of active commuting and leisure time exercise in overweight and obese women and men: A randomized controlled trial

Background and aimsPhysical inactivity is linked to low-grade inflammation, endothelial dysfunction and cardiovascular disease. We aimed to determine effects of active commuting and leisure time exercise on markers of low-grade inflammation and endothelial function in overweight and obese women and men. MethodsWe randomized 130 younger (20–45 years), physically inactive, healthy, overweight and obese (BMI: 25–35 kg/m2) women and men recruited from the Copenhagen area, Denmark, to either 6 months of habitual lifestyle (CON, n = 18), active commuting (BIKE, n = 35), or leisure time exercise of moderate (MOD, ∼50% VO2peak, n = 39) or vigorous intensity (VIG, ∼70% VO2peak, n = 38). Fasting blood samples were collected at baseline, 3, and 6 months and analyzed for concentrations of C-reactive protein (CRP), fibrinogen, von Willebrand factor (vWF), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1), and 90 participants (CON, n = 16; BIKE, n = 19; MOD, n = 31, VIG, n = 24) were included in a per-protocol analysis. ResultsWe observed lower concentrations of CRP in MOD compared with CON at 6 months (p = 0.013) and within-group decreases in CRP in BIKE (3 months: p = 0.045) and MOD (3 months: p = 0.061; 6 months: p = 0.038) corresponding to a 30% decrease in BIKE and 19% in MOD from baseline till 6 months. No effects of exercise were observed on fibrinogen, vWF, t-PA, PAI-1 or the t-PA/PAI-1 ratio within or between groups. ConclusionsOur findings suggest an anti-inflammatory effect of active commuting and moderate, but not vigorous, intensity leisure time exercise, but no alterations in endothelial function during 6 months of intervention.

Physiology and pathophysiology of the plasminogen system in the kidney.

The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPAand uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors α2-antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-RKT), and tPA, most evident in the endothelium. Plasmin may exert effects through protease-activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression.

Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-β and Cardiac Fibrosis.

Fibrosis is the pathological consequence of stress-induced tissue remodeling and matrix accumulation. Increased levels of plasminogen activator inhibitor type I (PAI-1) have been shown to promote fibrosis in multiple organ systems. Paradoxically, homozygous genetic deficiency of PAI-1 is associated with spontaneous age-dependent, cardiac-selective fibrosis in mice. We have identified a novel PAI-1-dependent mechanism that regulates cardiomyocyte-derived fibrogenic signals and cardiac transcriptional pathways during injury. Cardiac fibrosis in subjects with homozygous mutation in SERPINE-1 was evaluated with late gadolinium-enhanced cardiac magnetic resonance imaging. A murine cardiac injury model was performed by subcutaneous infusion of either saline or Angiotensin II by osmotic minipumps. We evaluated blood pressure, cardiac function (by echocardiography), fibrosis (with Masson Trichrome staining), and apoptosis (with TUNEL staining), and we performed transcriptome analysis (with RNA sequencing). We further evaluated fibrotic signaling in isolated murine primary ventricular myocytes. Cardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in SERPINE-1. In addition to its suppressive role during spontaneous cardiac fibrosis in multiple species, we hypothesized that PAI-1 also regulates fibrosis during cardiac injury. Treatment of young PAI-1-/- mice with Angiotensin II induced extensive hypertrophy and fibrotic cardiomyopathy, with increased cardiac apoptosis and both reactive and replacement fibrosis. Although Angiotensin II-induced hypertension was blunted in PAI-1-/- mice, cardiac hypertrophy was accelerated. Furthermore, ventricular myocytes were found to be an important source of cardiac transforming growth factor-β (TGF-β) and PAI-1 regulated TGF-β synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. Transcriptome analysis of ventricular RNA after Angiotensin II treatment confirmed that PAI-1 deficiency significantly enhanced multiple TGF-β signaling elements and transcriptional targets, including genes for extracellular matrix components, mediators of extracellular matrix remodeling, matricellular proteins, and cardiac integrins compared with wild-type mice. PAI-1 is an essential repressor of cardiac fibrosis in mammals. We define a novel cardiomyocyte-specific regulatory mechanism for TGF-β production by PAI-1, which explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-β axis and its early transcriptional effects that lead to myocardial fibrosis.