Elevated Plasminogen Activator Inhibitor-1 Research Articles

CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction

Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1 (PAI-1), a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (PAI-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis.

Heparin-binding protein and sepsis-induced coagulopathy: Modulation of coagulation and fibrinolysis via the TGF-β signalling pathway

BackgroundHeparin-binding protein (HBP) levels have been linked to organ failure and may represent an inflammatory biomarker of sepsis. We found disseminated intravascular coagulation (DIC) is associated with higher HBP levels in patients and in in vivo and in vitro models. This prospective, single-center observational study investigated the effects and underlying mechanisms of HBP on the coagulation cascade in sepsis. Methods538 patients with sepsis from June 2016 to December 2019 were enrolled. Mechanisms underlying HBP and the coagulation system were investigated in human umbilical vein endothelial cells (HUVEC) and C57 mice. ResultsIncreased HBP was associated with sepsis-induced DIC. The optimal cutoff value was 37.5 ng/mL (sensitivity: 56 %, specificity: 65 %). Antithrombin-III (AT-III) activity, plasmin-a2 plasmin inhibitor complex (PIC), procalcitonin (PCT), hemoglobin, and HBP ≥37.5 ng/mL were associated with of DIC occurrence. In HUVECs &C57 mice models, Western blotting, qPCR, and immunohistochemistry analysis showed that the binding between HBP and TGF-β receptor 2 (TGFBR2) caused elevation of plasminogen activator inhibitor-1 (PAI-1) levels. Furthermore, we found that mice stimulated with HBP had higher levels of fibrinogen and D-dimer in the blood. HBP treatment caused the accumulation of fibrinogen in mice lung tissue. Treatment with TGFBR2-small interfering RNAs inhibited the effects. ConclusionPatients with sepsis having HBP ≥37.5 ng/mL at admission were more likely to develop DIC. HBP upregulates the expression of fibrinogen and PAI-1 via TGFBR2 and the TGF-β signalling pathway.

Blood PAI-1 and cardiovascular and metabolic risk factors among the middle-aged women from SWAN study

The research on the role of plasminogen activator inhibitor-1 (PAI-1) in cardiovascular and metabolic diseases is insufficient. We aimed to explore whether elevated blood PAI-1 levels are significantly related to increased cardiovascular and metabolic risk factors in a midlife women population. Data were obtained from baseline characteristics in Study of Women’s Health Across the Nation (SWAN) study. Multivariable linear regression models were performed to examine for the trends of associations between PAI-1 and cardiovascular and metabolic risk factors (systolic BP, diastolic BP, fasting blood glucose, insulin, HDL-C, LDL-C, TG and TC), respectively. Smooth curve demonstrated gradual upward trends on associations of blood PAI-1 levels with LDL-C, TG, TC, fasting blood glucose, insulin, systolic BP and diastolic BP (all P < 0.05) and a gradual downward trend of PAI-1 levels with HDL-C (P < 0.05). Multivariable linear regression models still indicated that increased blood PAI-1 levels were associated with higher cardiovascular and metabolic risk after confounding factors including age, race/ethnicity, ever smoked regularly, alcohol in last 24 h, menopausal status, total family income and BMI were controlled for. Moreover, we observed that the independent associations between blood levels of PAI-1 and cardiovascular and metabolic risk factors examined by stratified analysis were not influenced by age, smoking status, menopausal status and BMI, respectively. Our analysis showed that increased blood PAI-1 levels were associated with higher level for cardiovascular and metabolic risk factors which mainly causes to higher possibility of cardio-cerebrovascular diseases in a large-sample midlife women subjects.

PAI1 Regulates Cell Morphology and Migration Markers in Trastuzumab-Resistant HER2-Positive Breast Cancer Cells.

HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast cancer. Trastuzumab resistance poses a significant challenge in clinical management due to its association with aggressive disease behaviour and limited treatment options. This study focuses on PAI1, a key player in the TGF-β signalling pathway, which is implicated in cancer progression and metastasis. Trastuzumab-resistant cell lines (SKBR3 and HCC1954) demonstrated markedly elevated PAI1 expression levels, up to 40-fold compared to parental lines. This elevation was accompanied by increased expression of migration markers such as Col4a1, Fibronectin, ICAM1, Timp2, and Vimentin. Through overexpression and silencing experiments, we observed that modulating PAI1 levels significantly impacts cell morphology, transitioning cells from an epithelial to mesenchymal phenotype. Importantly, combining trastuzumab with aleplasinin, a PAI1 inhibitor, synergistically reduced PAI1 expression in both parental and resistant cell lines. This suggests a potential therapeutic strategy to overcome trastuzumab resistance. These findings emphasise PAI1 as a critical mediator of migration and therapeutic response in HER2-positive breast cancer, offering insights into novel treatment approaches targeting PAI1 to improve clinical outcomes in drug resistance.

Prostaglandin E2 regulates the plasminogen activator pathway in human endometrial endothelial cells: a new in vitro model to investigate heavy menstrual bleeding

To study the role of PGE2 in regulating plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human primary endometrial endothelial cells (HEECs) from women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB). In vitro study using endometrial endothelial cells. Research laboratory setting. Women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB) provided endometrial biopsy samples. PGE2 and PGE2 receptor-selective agonists were administered to cultured HEECs. Levels of PAI-1 and tPA in NMB-HEECs and HMB-HEECs after treatment with PGE2 and receptor-selective agonists. PGE2 increased total PAI-1 levels in NMB-HEECs, but not in HMB-HEECs, which had higher baseline PAI-1 levels. PTGER1 and PTGER2 agonists increased PAI-1 in NMB-HEECs, while PTGER3 and PTGER4 did not. PGE2 had no effect on tPA levels in either NMB-HEECs or HMB-HEECs. PGE2, through PTGER1 and PTGER2, regulates the plasminogen activator system in NMB-HEECs, suggesting a role in reducing fibrinolytic activity during normal menstrual cycles. The lack of PGE2 effect and elevated baseline PAI-1 in HMB-HEECs support using this in vitro model to further understand prostaglandin pathways in normal and heavy menstrual bleeding.

Elevated carbonylated proteins are associated with major cardiovascular events in patients with chronic coronary syndrome: A cohort study.

Protein carbonylation is reported in atherosclerosis, but its predictive value is unknown. We evaluated plasma carbonylated protein (PC) levels in association with clinical outcomes in coronary artery disease (CAD) in long-term follow-up. In patients with advanced stable CAD, we assessed plasma PC content along with fibrin clot properties, i.e., permeability (Ks) and clot lysis time, and its determinants: plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor. We recorded a composite of myocardial infarction, ischemic stroke, systemic embolism, and cardiovascular death during a follow-up of 8.3 (1.8) years. The analysis involved 178 patients aged 64.0 (57.0-70.0) years. The baseline PC content was 2.9 (2.2-3.7) nmol/mg protein and was elevated above the reference value obtained for a control group (2.03 nmol/mg protein) in 82.6% of patients. In linear regression models, high PC adjusted for age was associated with lower Ks, longer clot lysis time, and elevated PAI-1 and thrombin-activatable fibrinolysis inhibitor. Baseline PC was 48% higher in patients with the composite endpoint (n = 67, 37.6%) compared with others (P <0.001). Patients with PC in the highest quartile (3.7-5.1 nmol/mg protein) were more likely to develop the composite endpoint compared to the lowest quartile (hazard ratio [HR] 4.9; 95% confidence interval, 2.1-11.3; P <0.001). This is the first study showing that in CAD the extent of protein carbonylation, in part via its antifibrinolytic effects, predisposes to cardiovascular events in long-term follow-up, highlighting the role of persistent oxidative protein modifications in atherosclerotic vascular disease.

Abstract 13625: Laboratory Markers of Effective Endogenous Fibrinolysis in Intermediate-High-Risk Pulmonary Embolism

Introduction: Unselected therapy with fibrinolysis in intermediate risk-pulmonary embolism (iPE) is associated with an unacceptable risk of bleeding. Early identification of iPE patients on anticoagulant therapy with ineffective endogenous fibrinolysis (eFL) could optimize treatment-strategy. Aims: The study aims to determine markers of (in)effective eFL in intermediate-risk PE initially on anticoagulant therapy with UFH. Methods: In course of 24 months, iPE patients were enrolled in the prospective study. At admission, and every 24 hours until day 5, levels of 6 selected markers of eFL (i.e., PAI-1 and tPA active assay and total antigen, TAFI, and PAP) were determined. Upon arrival and following a span of 36 hours,defined i) Clinical (heart rate &gt;100 bpm and spontaneous oxygen saturation &lt;90%), ii) Echo (D-shape, RVd/LVd from PLAX&gt;0.7, RV/RA &gt;30mmHg), and iii) CT (RV/LV&gt;0.9) variables were obtained. An (un)successful therapy was assessed by one point for each clinical, Echo and CT criteria, as at least one parameter from initially altered has adjusted at 36 hours. We performed correlation of laboratory markers with the dynamics of clinical and imaging characteristics. Results: Study population consists of 44 patients, 22 men, mean (SD) age 60 (18.3) yr., first (38), repeat (6) PE. Plasminogen activator inhibitor-1 (PAI-1) active assay showed the most promising results. The cut-off for unsuccessful therapy from AUC for PAI-1 was ≥65 U/ml. Mean (IQR) levels of PAI-1 on day 1 were 119 U/ml (27.1 - 155.8) and were significantly higher on day 1 (p=0.019) and day 2 (p=0.055) in those with/without adjustment of initial pathological findings. PAI-1 elevation was associated with unsuccessful restoration of clinical, Echo and CT parameters at 36 hours (Table1). Overall Tx failure was associated with elevated PAI-1 (p=0.011). Conclusions: PAI-1 active assay could help us in identifying patients who would benefit from early indicated therapeutic fibrinolysis.

Abstract 14009: Plasminogen Activator Inhibitor-1 (PAI-1) is an Essential Driver of Cardiovascular Aging in Mice

Introduction: PAI-1 is the protein product of the gene Serpine1 . PAI-1 is a key contributor to cellular senescence in humans and mice, and elevated PAI-1 predicts the development of aging-related disorders including Type 2 diabetes and hypertension. GrimAge, a composite measure of epigenetic age, includes a DNA methylation estimator of plasma PAI-1 levels that independently predicts the development of cardiovascular (CV) morbidity including hypertension and time to heart failure. While many mechanistic contributions of PAI-1 to senescence and aging are well documented, its fundamental role in CV aging has not been fully investigated. Hypothesis: PAI-1 overexpression in mice promotes CV aging, while PAI-1 deficiency attenuates this phenotype in the presence of a stressor. Methods: To assess the effect of PAI-1 overexpression on CV aging, mice transgenic for a stable variant of human PAI-1 (n=14 transgenics, n=8 wild-type littermates) were characterized at 2 months and 7 months. To assess the effect of PAI-1 deficiency, mice heterozygous for a Serpine1 frame-shifting loss-of-function mutation (n=9) and wild-type littermates (n=10) were assessed; these mice underwent cardiovascular stress using N(ω)-nitro-L-arginine methyl ester (L-NAME) (1mg/L) for 8 weeks. Cardiovascular phenotyping included treadmill, pulse-wave velocity (PWV), echocardiography, and blood pressure (BP) measurement at the beginning and end of study. Histology was performed on aortas using Masson’s Trichome and analyzed for fibrosis quantification. Results: PAI-1 transgenic mice exhibited worse diastolic (E/e’) and vascular function (PWV, systolic and diastolic BP) compared to their wild-type counterparts. Histology showed more extensive peri-aortic fibrosis. In contrast, PAI-1 loss-of-function heterozygotes were broadly resistant to the vascular aging effects of L-NAME compared to wild-type mice. Molecular profiling of vascular tissues collected from animals is underway and includes bulk aorta RNAseq and measures of epigenetic age. Conclusion: PAI-1 is necessary and sufficient for the development of a CV aging phenotype in mice while PAI-1 deficiency attenuates stress-induced CV aging. Inhibition of PAI-1 will likely be tested for preventing CV aging in humans.

Plasma plasminogen activator inhibitor-1 as a predictive marker of type 2 diabetic nephropathy in Egyptian patients

Background The study investigates the relationship between Plasminogen activator inhibitor-1 (PAI-1) levels and the progression of diabetic nephropathy (DN). The fibrinolytic system is impaired in type 2 diabetes mellitus (DM), leading to elevated PAI-1 levels, increasing the potential for renal fibrosis and worsening nephropathy. Patients and methods The research involved 196 type 2 DM patients and 50 healthy control individuals divided into four groups based on Urinary albumin excretion (UAE). Results The diabetic group had significantly higher PAI-1 levels than the control group. The study also found that diabetic patients with macroalbuminuria had higher PAI-1 levels than the control group. Patients with higher UAE and PAI-1 levels had significantly higher serum creatinine concentrations. The study found a significant negative link with creatinine clearance and a significant positive correlation between PAI-1 and serum creatinine and 24-h urine albumin in terms of PAI-1. Conclusions There was a notable positive association with the 24-h UAE, suggesting that increases in PAI-1 were linked to a decline in renal function.

Dual deletion of guanylyl cyclase-A and p38 mitogen-activated protein kinase in podocytes with aldosterone administration causes glomerular intra-capillary thrombi

Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. Invitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor- β1 (TGF-β1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-β1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.

Elevated PAI-1 Levels Are Associated With Severe COVID-19

A growing body of evidence points to endothelial dysfunction in severe COVID-19 cases. Plasminogen activator inhibitor-1 (PAI-1) is a marker of endothelial injury and correlates with severe uncontrolled asthma. PAI-1 could be a candidate as a prognostic marker of COVID-19-related hospitalization and clinical outcomes. Therefore, the association between PAI-1 and the severity of COVID-19 was investigated.

Plasminogen Activator Inhibitor-1 as a Marker of Thrombosis among Prehypertensive Patients: A Cross-sectional Study

Introduction: Impaired endogenous fibrinolysis has been shown to play a role in the pathogenesis and complications of hypertension. Plasminogen Activator Inhibitor-1 (PAI-1) is said to be a predictor of impaired fibrinolysis and thrombosis. Prehypertension is a common worldwide condition and is known to be an independent risk factor for Cardiovascular Disease (CVD). Aim: Present study aimed to measure plasma PAI-1 levels in prehypertensive patients and normal subjects and to find the correlation between elevated PAI-1 levels with Blood Pressure (BP), triglycerides, total cholesterol, Low-Density Lipoproteins (LDL) cholesterol, High-Density Lipoproteins (HDL) cholesterol, and urine albumin. Materials and Methods: This cross-sectional analytical study included 100 patients, comprising 50 prehypertensive individuals and 50 controls, aged between 35 and 50 years. The study was conducted at Sapthagiri Institute of Medical Sciences and Research Centre in Bangalore, India. Anthropometric measurements, PAI-1 levels, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and urine albumin were measured using standard procedures. The data were statistically analysed using the Statistical Package for Social Sciences (SPSS) version 10.0, applying Student t-test and Chisquare test. Correlation analysis was performed to assess the relationship between PAI-1 and various parameters. Results: A total of 100 patients were included in the study which had 64 men and 36 women with a mean age of 46±7 years. PAI-1 levels were significantly higher in the prehypertensive group compared to the control group (p-value=0.013). Participants with higher plasma PAI-1 levels had significantly elevated BP (p-value=0.001) compared to those with lower PAI-1 levels. Total cholesterol, triglycerides, and LDL cholesterol were significantly increased in prehypertensive individuals (p-value=0.001), whereas HDL cholesterol was significantly lower (p-value=0.001). The study also observed a significant increase in urine albumin in the prehypertensive group with elevated PAI-1 levels compared to the controls (p-value=0.001). The study revealed that elevated plasma PAI-1 levels did not show a significant positive correlation with SBP and DBP (r=0.138 and 0.660, p-value of 0.338 and 0.648, respectively). Plasma PAI-1 levels were weakly correlated with total cholesterol (r=0.145, p-value 0.315), LDL cholesterol (r=-0.068, p-value 0.640), HDL cholesterol (r=0.21, p-value 0.882), and triglycerides (r=0.207, p-value 0.150). There was no significant correlation between increased PAI-1 levels and urine albumin (r=-0.225, p-value of 0.117). Conclusion: Present study demonstrated that plasma PAI-1, total cholesterol, triglycerides, LDL cholesterol, and urine albumin were significantly elevated in prehypertensive individuals, suggesting vascular damage and inflammation. As prehypertension is often asymptomatic, patients with prehypertension should be considered to have an increased risk for CVD.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis.

Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I² = 72%) and the chi-square test (χ² = 18.32; p = 0.003). This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Wnt5a/β-catenin axis is involved in the downregulation of AT2 lineage by PAI-1.

Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-β catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in Serpine1Tg mice. Elevated PAI-1 level suppressed organoid number, development efficiency, and total surface area in vitro. Anti-PAI-1 neutralizing antibody restored organoid number, proliferation and differentiation of AT2 cells, and β-catenin level in organoids. Both Wnt family member 5A (Wnt5a) and Wnt5a-derived N-butyloxycarbonyl hexapeptide (Box5) altered the lineage of AT2 cells. This study demonstrates that elevated PAI-1 regulates AT2 proliferation and differentiation via the Wnt5a/β catenin cascades. PAI-1 could serve as autocrine signaling for lung injury repair.

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.

Ibudilast Reduces IL-6 Levels and Ameliorates Symptoms in Lipopolysaccharide-Induced Sepsis Mice.

In Japan, ibudilast (IBD) is a therapeutic agent used to treat asthma, allergic conjunctivitis, and dizziness caused by cerebrovascular disease. Previously, we have reported that IBD could reduce the secretion of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, in lipopolysaccharide (LPS)-treated RAW264.7 monocyte-linage cells in vitro. In the present study, we examined the anti-inflammatory effects of IBD in vivo. As IL-6 is a biomarker for sepsis and has been suggested to exacerbate symptoms, we determined whether IBD reduces IL-6 levels in vivo and improves sepsis symptoms in animal models. We observed that IBD treatment reduced IL-6 levels in the lungs of LPS-treated mice and improved LPS-induced hypothermia, one of the symptoms of sepsis. In addition, IBD reduced IL-6 and attenuated plasminogen activator inhibitor-1 (PAI-1) and alanine aminotransferase (ALT) levels in the serum of LPS-treated mice. Elevated PAI-1 levels exacerbate sepsis-induced disseminated intravascular coagulation (DIC), and ALT is a biomarker for liver dysfunction. IBD improved the survival of mice administered a lethal dose of LPS. IBD administration ameliorated kidney pathology of model mice. Overall, these results suggest that IBD exerts anti-inflammatory functions in vivo and could be a drug candidate for treating endotoxemia, including sepsis.

Plasminogen Activator Inhibitor-1 Levels in Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Several studies have investigated the role of multiple proteins in nonalcoholic fatty liver disease (NAFLD); one that has recently gained attention is plasminogen activator inhibitor-1 (PAI-1). However, studies evaluating PAI-1 levels in NAFLD demonstrated conflicting results. Our objective was to understand the role of PAI-1 in NAFLD more clearly by carrying out a systematic review and meta-analysis. We gathered evidence by performing a systematic search on PubMed, EMBASE, and Cochrane Library, through using a predefined search string. The included studies diagnosed NAFLD through either liver biopsy, ultrasonography, computed tomography (CT), magnetic resonance spectroscopy, or using one of the latter methods with blood parameters. Studies had to fulfill predefined inclusion and exclusion criteria. To assess the quality of the studies included, we used the NHLBI quality assessment tools. The main summary outcome was the mean difference (MD) in serum PAI-1 levels reported as ng/mL Results: 33 articles involving 10,840 subjects fulfilled our inclusion criteria and were systematically reviewed. 11 studies were included in our meta-analyses. We found a significant MD in PAI-1 levels in NAFLD patients vs. controls [17.147 (95%CI: 7.720-26.574)]. Moreover, subgroup analysis evaluating PAI-1 levels in biopsy- proven NAFLD vs. controls remained significant [24.086 (95%CI: 3.812-44.361)], as well as in CT-diagnosed NAFLD [15.523 (95%CI: 7.163-23.883)]. However, no significant MD in PAI-1 levels was found in ultrasound- diagnosed NAFLD patients vs. controls [10.394 (95%CI: -13.335-34.123)]. No significant MD in PAI-1 levels in NASH patients vs. controls was observed [26.835 (95%CI: -0.879-54.549)]. In summary, elevated serum PAI-1 levels are associated with adult NAFLD (biopsy-proven and CT-diagnosed). However, no significant difference was found in ultrasound-diagnosed NAFLD and NASH patients. Nonetheless, the included studies have methodological variance, dictating that the obtained results should be carefully interpreted.

This Month in Anesthesiology

This Month in Anesthesiology

PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea?

Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.

SARS-CoV-2 infection induces soluble platelet activation markers and PAI-1 in the early moderate stage of COVID-19.

IntroductionCoagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID‐19. However, it is unclear when particularly platelet activation markers and coagulation factors dysregulated during the pathogenesis of COVID‐19. Here, we sought to assess the levels of coagulation and platelet activation markers at moderate and severe stages of COVID‐19 to understand the pathogenesis.MethodsTo understand this, hospitalized COVID‐19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases) were recruited. Phenotypic and molecular characterizations were performed employing basic coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT), D‐Dimer, and tissue factor pathway inhibitor (TFPI). The flow cytometry‐based multiplex assays were performed to assess FXI, anti‐thrombin, prothrombin, fibrinogen, FXIII, P‐selectin, sCD40L, plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor‐1 (PAI‐1), and D‐Dimer.ResultsThe investigations revealed induction of plasma P‐selectin and CD40 ligand (sCD40L) in moderate COVID‐19 cases, which were significantly abolished with the progression of COVID‐19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID‐19. Further analysis revealed fibrinogen induction in both moderate and severe patients. Interestingly, an elevated PAI‐1 more prominently in moderate, and tPA particularly in severe COVID‐19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of the disease.ConclusionsIn summary, induction of soluble P‐selectin, sCD40L, fibrinogen, and PAI‐1 suggests the activation of platelets and coagulation system at the moderate stage before COVID‐19 patients require intensive care. These findings would help in designing better thromboprophylaxis to limit the COVID‐19 severity.