Gasotransmitter CO Attenuates Bleomycin-Induced Fibroblast Senescence via Induction of Stress Granule Formation

Cellular senescence is recognized as a phenomenon wherein a proliferative cell undergoes a permanent growth arrest. The accumulation of senescent cells over time can become harmful and result in diseases and physiological decline. Plasminogen activator inhibitor (PAI-1) is considered as a critical marker and mediator of cellular senescence. The formation of stress granules (SGs) could prevent senescence through the sequestration of PAI-1, and we previously suggested that exogenous carbon monoxide (CO) could induce SG assembly via integrated stress response (ISR). Although CO is known to possess anti-inflammatory, antioxidative, and antiapoptotic properties, whether it exerts antisenescent effect is still not well defined. Here, to address whether CO-induced SGs could protect against cellular senescence, we first treated lung fibroblasts with bleomycin (BLM) to establish DNA damage-induced cellular senescence, and observed a significant increase of several hallmarks of senescence through SA-β-gal staining, immunofluorescence, qRT-PCR, and Western blot assay. However, pre- and posttreatment of CO could remarkably attenuate these senescent phenotypes. According to our immunofluorescence results, CO-induced SGs could inhibit BLM-induced cellular senescence via sequestration of PAI-1, while it was abolished after the cotreatment of ISR inhibitor (ISRIB) due to the inhibition of SG assembly. Overall, our results proposed a novel role of CO in suppressing bleomycin-induced lung fibroblast senescence through the assembly of SGs.

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Role of fibrinolytic parameters and plasminogen activator inhibitor 1 (PAI-1) promoter polymorphism on premature atherosclerosis in SLE patients

Lupus ◽

10.1177/0961203311404911 ◽

2011 ◽

Vol 20 (10) ◽

pp. 1063-1071 ◽

Cited By ~ 7

Author(s):

M Bicakcigil ◽

DA Tasan ◽

N Tasdelen ◽

N Mutlu ◽

S Yavuz

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Promoter Polymorphism ◽

Plasminogen Activator Inhibitor 1 ◽

Premature Atherosclerosis ◽

Fibrinolytic Parameters ◽

Activator Inhibitor ◽

Pai 1

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Emerging Role of Endothelial and Inflammatory Markers in Preeclampsia

Disease Markers ◽

10.1155/2009/658943 ◽

2009 ◽

Vol 26 (3) ◽

pp. 127-133 ◽

Cited By ~ 6

Author(s):

Menha Swellam ◽

Nervana Samy ◽

Susan Abdl Wahab ◽

Mohamed Saeed Ibrahim

Keyword(s):

Inflammatory Markers ◽

Linear Regression Analysis ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

New Approach ◽

Reactive Protein ◽

Diagnostic Role ◽

Activator Inhibitor ◽

Pai 1

Objectives:Endothelial disturbance and excess inflammatory response are pathogenic mechanisms in pre-eclampsia (PE). Authors determine the clinical diagnostic role for thrombomodulin (TM), plasminogen activator inhibitor-1 (PAI-1) as endothelial markers and C-reactive protein (CRP), and interlukin-6 (IL-6) as inflammatory markers when tested independently or in combinations.Materials and methods:We conducted a retrospective study in a cohort of 185 women grouped as 80 women with PE, 55 normotensive pregnant and 50 healthy non-pregnant. Plasma levels of TM, PAI-1, CRP and IL-6 were examined using enzyme linked immunosorbent assays.Results:Median levels and the positivity rates for the investigated markers were higher in PE as compared to the other groups (P< 0.0001). Using linear regression analysis, the investigated markers were significantly correlated regarding healthy nonpregnantvsPE or normotensive pregnantvsPE. The sensitivity of PAI-1 was the highest (98%) among the tested biomarkers. Combination between the investigated markers revealed absolute sensitivity (100%) and reliable specificity especially when PAI-1 was combined with CRP at 83% specificity.Conclusions:Investigated endothelial and inflammatory markers revealed sensitive diagnostic test for PE. However, coupled combination between PAI-1 with CRP showed superior both sensitivity and specificity which represent a promising new approach for detection of PE.

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Role of plasminogen activator inhibitor-1 gene polymorphisms in osteoporosis: A study in Chinese post-menopausal women

European Journal of Inflammation ◽

10.1177/2058739218767292 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876729

Author(s):

An Wan ◽

Daodong Liu

Keyword(s):

Gene Polymorphisms ◽

Chinese Women ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Chain Reaction ◽

Polymerase Chain ◽

Post Menopausal ◽

Activator Inhibitor ◽

Pai 1

Osteoporosis is a chronic multifactorial disease characterized by deterioration of bone mass and is vulnerable to bone fracture. Plasminogen activator inhibitor-1 (PAI-1) is an important molecule for maintenance of optimum bone mass. Several single-nucleotide polymorphisms (SNPs) in PAI-1 have been reported to alter PAI-1 expression and/or the translational level. In this report, we explored the possible role of common PAI-1 gene polymorphisms on predisposition to osteoporosis in a Chinese cohort. A total of 364 post-menopausal Chinese women diagnosed of having osteoporosis and 350 healthy females hailing from similar areas were enrolled in this study. Five common SNPs (−844G > A, −6754G/5G, +43G > A, +9785G > A and +11053T > G) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Relative expression of PAI-1 mRNA and plasma PAI-1 levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Prevalence of homozygous mutant (5G/5G) and minor allele (5G) of PAI-1 (−675 4G/5G) polymorphism was significantly more frequent in patients than in healthy controls (5G/5G: P < 0.0001, odds ratio (OR) = 3.18; 5G: P < 0.0001, OR = 1.65). Both plasma PAI-1 and relative mRNA expression levels were significantly lower in patients compared to healthy controls. Interestingly, the quantity of plasma PAI-1 and mRNA expression was correlated with PAI-1 (−675 4G/5G) polymorphism: subjects with 4G/4G genotype had elevated PAI-1 in comparison to homozygous mutant, and displayed lower quantity of PAI-1 protein and mRNA values. PAI-1 (−675 4G/5G) mutant is associated with susceptibility to development of osteoporosis in post-menopausal Chinese women. Furthermore, this variant in the promoter region alters plasma protein levels and relative expression of PAI-1.

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Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay

Blood ◽

10.1182/blood.v71.1.220.bloodjournal711220 ◽

1988 ◽

Vol 71 (1) ◽

pp. 220-225 ◽

Cited By ~ 325

Author(s):

PJ Declerck ◽

MC Alessi ◽

M Verstreken ◽

EK Kruithof ◽

I Juhan-Vague ◽

...

Keyword(s):

Plasminogen Activator ◽

Immunosorbent Assay ◽

Healthy Subjects ◽

Plasminogen Activator Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Plasminogen Activator Inhibitor 1 ◽

Platelet Poor Plasma ◽

Activator Inhibitor ◽

Pai 1

An enzyme-linked immunosorbent assay for plasminogen activator inhibitor-1 (PAI-1) in biologic fluids was developed on the basis of two murine monoclonal antibodies raised against PAI-1 purified from HT- 1080 fibrosarcoma cells. The lower limit of sensitivity of the assay in plasma is 2 ng/mL. The assay is 12 times less sensitive toward the PAI- 1/human tissue-type plasminogen activator (t-PA) complex as compared with free PAI-1. The intraassay, interassay, and interdilution coefficients of variation are 5.2%, 8.0%, and 7.1%, respectively. The level of PAI-1 in platelet-poor plasma of healthy subjects is 18 +/- 10 ng/mL (mean +/- SD, n = 45). In platelet-rich plasma after freezing and thawing, 92% of PAI-1 antigen is released from platelets, whereas only 8% is found in the corresponding platelet-poor plasma. In platelet-poor plasma from healthy subjects, a linear correlation (r = 0.80) was found between PAI activity and PAI-1 antigen. In plasma approximately two thirds of the PAI-1 antigen was functionally active, whereas only 5% of the PAI-1 antigen released from platelets was active. During pregnancy a progressive increase of PAI-1 antigen levels up to three- to sixfold the control value was observed. In plasma of patients with recurrent deep vein thrombosis, PAI-1 levels were 44 +/- 20 ng/mL (mean +/- SD, n = 7), during a clinically silent phase. Four of these patients had a level above 38 ng/mL (mean +/- 2 SD of normal). The present assay, based on stable and reproducible reagents, allows the specific determination of PAI-1 antigen in biologic fluids. It may facilitate interlaboratory comparisons and be useful for further investigations of the role of PAI-1 in clinical conditions associated with impaired fibrinolysis and/or a tendency to thrombosis and investigations of the role of PAI-1 in platelets.

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714 CRITICAL ROLE OF PLASMINOGEN ACTIVATOR INHIBITOR (PAI-1) IN FRUCTOSE-INDUCED NON- ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Journal of Hepatology ◽

10.1016/s0168-8278(09)60716-9 ◽

2009 ◽

Vol 50 ◽

pp. S261

Author(s):

G. Kanuri ◽

A. Spruss ◽

S. Weber ◽

S. Wagneberger ◽

S.C. Bischoff ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Critical Role ◽

Plasminogen Activator Inhibitor ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Activator Inhibitor ◽

Pai 1

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Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay

Blood ◽

10.1182/blood.v71.1.220.220 ◽

1988 ◽

Vol 71 (1) ◽

pp. 220-225 ◽

Cited By ~ 72

Author(s):

PJ Declerck ◽

MC Alessi ◽

M Verstreken ◽

EK Kruithof ◽

I Juhan-Vague ◽

...

Keyword(s):

Plasminogen Activator ◽

Immunosorbent Assay ◽

Healthy Subjects ◽

Plasminogen Activator Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Plasminogen Activator Inhibitor 1 ◽

Platelet Poor Plasma ◽

Activator Inhibitor ◽

Pai 1

Abstract An enzyme-linked immunosorbent assay for plasminogen activator inhibitor-1 (PAI-1) in biologic fluids was developed on the basis of two murine monoclonal antibodies raised against PAI-1 purified from HT- 1080 fibrosarcoma cells. The lower limit of sensitivity of the assay in plasma is 2 ng/mL. The assay is 12 times less sensitive toward the PAI- 1/human tissue-type plasminogen activator (t-PA) complex as compared with free PAI-1. The intraassay, interassay, and interdilution coefficients of variation are 5.2%, 8.0%, and 7.1%, respectively. The level of PAI-1 in platelet-poor plasma of healthy subjects is 18 +/- 10 ng/mL (mean +/- SD, n = 45). In platelet-rich plasma after freezing and thawing, 92% of PAI-1 antigen is released from platelets, whereas only 8% is found in the corresponding platelet-poor plasma. In platelet-poor plasma from healthy subjects, a linear correlation (r = 0.80) was found between PAI activity and PAI-1 antigen. In plasma approximately two thirds of the PAI-1 antigen was functionally active, whereas only 5% of the PAI-1 antigen released from platelets was active. During pregnancy a progressive increase of PAI-1 antigen levels up to three- to sixfold the control value was observed. In plasma of patients with recurrent deep vein thrombosis, PAI-1 levels were 44 +/- 20 ng/mL (mean +/- SD, n = 7), during a clinically silent phase. Four of these patients had a level above 38 ng/mL (mean +/- 2 SD of normal). The present assay, based on stable and reproducible reagents, allows the specific determination of PAI-1 antigen in biologic fluids. It may facilitate interlaboratory comparisons and be useful for further investigations of the role of PAI-1 in clinical conditions associated with impaired fibrinolysis and/or a tendency to thrombosis and investigations of the role of PAI-1 in platelets.

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The role of activator protein-1 (ap-1) in the protein kinase c (pkc)-mediated expression of plasminogen activator inhibitor i (PAI-1) in hep g2 cells

Fibrinolysis and Proteolysis ◽

10.1016/0268-9499(94)90618-1 ◽

1994 ◽

Vol 8 ◽

pp. 119

Author(s):

J. Arts ◽

J. Grimbergen ◽

P. Bosma ◽

T. Kooistra

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Plasminogen Activator Inhibitor ◽

Activator Protein 1 ◽

Hep G2 ◽

Hep G2 Cells ◽

Kinase C ◽

Activator Inhibitor ◽

Pai 1

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Plasminogen activator inhibitor-1 and tumour growth, invasion, and metastasis

Thrombosis and Haemostasis ◽

10.1160/th03-12-0784 ◽

2004 ◽

Vol 91 (03) ◽

pp. 438-449 ◽

Cited By ~ 98

Author(s):

Michelle Durand ◽

Julie Bødker ◽

Anni Christensen ◽

Daniel Dupont ◽

Martin Hansen ◽

...

Keyword(s):

Plasminogen Activator ◽

Molecular Interactions ◽

Plasminogen Activator Inhibitor ◽

Biological Functions ◽

Invasion And Metastasis ◽

Plasminogen Activator Inhibitor 1 ◽

Human Tumours ◽

Activator Inhibitor ◽

Pai 1

SummaryIn recent decades, evidence has been accumulating showing the important role of urokinase-type plasminogen activator (uPA) in growth, invasion, and metastasis of malignant tumours. The evidence comes from results with animal tumour models and from the observation that a high level of uPA in human tumours is associated with a poor patient prognosis. It therefore initially came as a surprise that a high tumour level of the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) is also associated with a poor prognosis, the PAI-1 level in fact being one of the most informative biochemical prognostic markers. We review here recent investigations into the possible tumour biological role of PAI-1, performed by animal tumour models, histological examination of human tumours, and new knowledge about the molecular interactions of PAI-1 possibly underlying its tumour biological functions. The exact tumour biological functions of PAI-1 remain uncertain but PAI-1 seems to be multifunctional as PAI-1 is expressed by multiple cell types and has multiple molecular interactions. The potential utilisation of PAI-1 as a target for anti-cancer therapy depends on further mapping of these functions.

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