Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus.

Auwerx, Johan; Bouillon, Roger; Collen, D.; Geboers, J.

doi:10.1161/01.atv.8.1.68

Cited by 288 publications

(135 citation statements)

References 19 publications

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“…Although the AGE effects appeared to be modest, we speculate that chronic exposure to AGE during prolonged hyperglycaemia causes blood vessels to become more susceptible to fibrin formation and stabilization. Actually, a decrease of approximately 30 % in plasma PGI 2 was a risk factor for diabetic vascular complications [38], and about a one and one halffold increase in plasma PAI-1 activity resulted in an impaired fibrinolytic capacity in various thrombogenic disorders [6,8,10]. In addition, a synergistic involvement of glucose and AGE on reduced fibrinolysis was suggested by Maiello et al [39] who showed that high glucose increased the PAI-1 activity in HU-VEC by approximately 120 %.…”

Section: Discussionmentioning

confidence: 98%

“…Although epidemiological studies have established the plasma PAI-1 elevation in diabetes [9,10], there is no clinical evidence suggesting plasma AGE concentrations as a major contributor to the PAI-1 concentration. Further studies would be required to determine a cause-to-effect relationship between AGE and PAI-1 in diabetic patients, including intervention studies with AGE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

et al. 1998

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Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure which are common complications in patients with prolonged diabetes [1±3]. Plasminogen activator inhibitor-1 (PAI-1) is an important fast-acting serine protease inhibitor that attenuates fibrinolysis [4]. Epidemiological studies have demonstrated that reduced fibrinolytic activity because of elevated plasma PAI-1 is an important factor in various thrombotic diseases such as deep vein thrombosis, ischaemic heart disease [5±8] and diabetic vascular complications [9±10]. In addition to the attenuated fibrinolytic activity, hypercoagulability and platelet hyperaggregation are also prevalent in diabetic patients, contributing to microthrombus formation in diabetic micro-and macroangiopathies [11]. The molecular mechanisms underlying these thrombogenic abnormalities, however, are not fully understood. Diabetologia (1998) Summary Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI 2 ), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI 2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI 2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI 2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications.[ Diabetologia (1998

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

et al. 1998

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“…[37][38][39] Alterations in PAI-1 and other gene products merit further investigation as drug-eluting stents are applied more broadly as the antiproliferative and prothrombotic effects may be magnified or diminished in other vascular beds or in patients that constitutively overproduce PAI-1, such as Type 2 diabetics or patients with the metabolic syndrome. 40 …”

Section: Discussionmentioning

confidence: 99%

Antiproliferative Agents Alter Vascular Plasminogen Activator Inhibitor-1 Expression

Muldowney

Stringham

Levy

et al. 2007

ATVB

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Objectives-Drug eluting stents (DES) reduce the incidence of restenosis after coronary angioplasty. Enthusiasm has been tempered by a possible increased risk of in-stent thrombosis. We examined the effects of paclitaxel and rapamycin on the endothelial transcriptome to identify alterations in gene expression associated with thrombosis. Methods and Results-Gene expression profiling was performed on human coronary artery endothelial cells treated with rapamycin or paclitaxel. Plasminogen activator inhibitor-1 (PAI-1) was the most consistently induced transcript in rapamycin-treated human coronary artery endothelial cells. RT-PCR and ELISA were performed to confirm positive findings. Transgenic mice engineered to express enhanced green fluorescent protein under control of the human PAI-1 promoter were also treated. Rapamycin and paclitaxel treated endothelial cells produced dose-dependent increases in PAI-1. There was a variable effect on endothelial tissue-type plasminogen activator (t-PA) expression. Enhanced expression of PAI-1 and enhanced green fluorescent protein were detected in coronary arteries, the aorta, and kidney of the mice. Key Words: antiproliferative Ⅲ plasminogen activator inhibitor 1 Ⅲ rapamycin paclitaxel gene array Ⅲ endothelial cells Ⅲ gene expression R estenosis is widely recognized as a major factor limiting the long-term clinical efficacy of percutaneous coronary intervention. 1 The 30% to 50% incidence of restenosis associated with balloon angioplasty alone has been reduced in half by the use of bare metal stents. 2 Numerous mechanical and pharmacological strategies have failed to further reduce restenosis until recently. 3,4 The development of drug eluting stents (DES) that release small amounts of antiproliferative agents locally provides an effective strategy for reducing the risk of restenosis after angioplasty to levels below 10%. 5,6 These impressive effects on restenosis were tempered initially by concerns about possible increases in the rate of in stent thrombosis with DES. 7,8 Follow-up data from SIRIUS, and other recent trials appeared to alleviate these concerns. 9,10 Conclusion-Antiproliferative

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“…Although PAI-1 concentrations are elevated in the plasma of Type 2 diabetic patients [22,23], the effects of Type 1 diabetes mellitus on plasma PAI-1 levels are controversial. Some reports indicate that plasma PAI-1 levels are increased in Type 1 diabetic patients [24][25][26][27], whereas others indicate normal levels [22,[28][29][30]. However, the molecular mechanism of diabetes-induced PAI-1 expression has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

et al. 2005

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Diabetes is associated with an excess risk of cardiac events, and one of the risk factors for infarction is the elevated-levels of plasminogen activator inhibitor-1 (PAI-1). To evaluate how the molecular clock mechanism is involved in the diabetes-induced circadian augmentation of PAI-1 gene expression, we examined the expression profiles of PAI-1 mRNA in the hearts of Clock mutant mice with streptozotocin-induced diabetes. Circadian expression of PAI-1 mRNA was blunted to low levels under both normal and diabetic conditions in Clock mutant mice, although the expression rhythm was augmented in diabetic wild-type (WT) mice. Furthermore, plasma PAI-1 levels became significantly higher in WT mice than in Clock mutant mice after STZ administration. Our results suggested that the circadian clock component, CLOCK, is involved in the diabetes-induced circadian augmentation of PAI-1 expression in the mouse heart.

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Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus.

Cited by 288 publications

References 19 publications

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells

Antiproliferative Agents Alter Vascular Plasminogen Activator Inhibitor-1 Expression

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

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