Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Berry, Catherine; Lunven, Catherine; Lechaire, Irène; Girardot, C; O'Connor, Stephen E.

doi:10.1038/sj.bjp.0702030

Cited by 30 publications

(30 citation statements)

References 32 publications

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“…Although the efficiency of PAI-1 inhibition in vivo by monoclonal antibodies has been demonstrated in a number of studies [24,25], they were all tested in thrombosis models. Specifically, the antibody used in this experiment, MA-33H1F7, exhibited an effect in reducing thrombus formation in rat models [26,27]. However, this is the first time that these antibodies were tried in a laparoscopic mouse model and it may be that the absence of effect could be explained because the dose was not optimized.…”

Section: Discussionmentioning

confidence: 80%

Effect of Reteplase™ and PAI-1 antibodies on postoperative adhesion formation in a laparoscopic mouse model

et al. 2008

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Section: Discussionmentioning

confidence: 80%

Effect of Reteplase™ and PAI-1 antibodies on postoperative adhesion formation in a laparoscopic mouse model

et al. 2008

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“…MA-33H1F7 inhibits mouse and rat PAI-1 by converting PAI-1 to a noninhibitory substrate for tPA (16). The inhibiting efficacy of this antibody on PAI-1 has been demonstrated in vivo (6). The dose of anti-PAI-1 antibody was chosen on the basis of its biological activity in inhibiting PAI-1 effects on angiogenesis in vitro (46).…”

Section: Methodsmentioning

confidence: 99%

“…These differentiated 3T3-L1 adipocytes at day 6 exhibited intracellular lipid droplets and were used for this study. To inhibit PAI-1, 3T3-L1 preadipocytes were treated for 6 days with a neutralizing monoclonal antibody against PAI-1 (MA-33H1F7, 10 g/ml) along with induction of differentiation (6,7,15). MA-33H1F7 inhibits mouse and rat PAI-1 by converting PAI-1 to a noninhibitory substrate for tPA (16).…”

Section: Methodsmentioning

confidence: 99%

Plasminogen activator inhibitor-1 modulates adipocyte differentiation

Liang¹,

Kanjanabuch²,

Mao³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

114

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Increased plasminogen activator inhibitor-1 (PAI-1) is linked to obesity and insulin resistance. However, the functional role of PAI-1 in adipocytes is unknown. This study was designed to investigate effects and underlying mechanisms of PAI-1 on glucose uptake in adipocytes and on adipocyte differentiation. Using primary cultured adipocytes from PAI-1+/+ and PAI-1−/− mice, we found that PAI-1 deficiency promoted adipocyte differentiation, enhanced basal and insulin-stimulated glucose uptake, and protected against tumor necrosis factor-α-induced adipocyte dedifferentiation and insulin resistance. These beneficial effects were associated with upregulated glucose transporter 4 at basal and insulin-stimulated states and upregulated peroxisome proliferator-activated receptor-γ (PPARγ) and adiponectin along with downregulated resistin mRNA in differentiated PAI-1−/− vs. PAI-1+/+ adipocytes. Similarly, inhibition of PAI-1 with a neutralizing anti-PAI-1 antibody in differentiated 3T3-L1 adipocytes further promoted adipocyte differentiation and glucose uptake, which was associated with increased expression of transcription factors PPARγ, CCAAT enhancer-binding protein-α (C/EBPα), and the adipocyte-selective fatty acid-binding protein aP2, thus mimicking the phenotype in PAI-1−/− primary adipocytes. Conversely, overexpression of PAI-1 by adenovirus-mediated gene transfer in 3T3-L1 adipocytes inhibited differentiation and reduced PPARγ, C/EBPα, and aP2 expression. This was also associated with a decrease in urokinase-type plasminogen activator mRNA expression, decreased plasmin activity, and increased collagen I mRNA expression. Collectively, these results indicate that absence or inhibition of PAI-1 in adipocytes protects against insulin resistance by promoting glucose uptake and adipocyte differentiation via increased PPARγ expression. We postulate that these PAI-1 effects on adipocytes may, at least in part, be mediated via modulation of plasmin activity and extracellular matrix components.

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“…[17][18][19] MA-TCK26D6 modulates TAFI/TAFIa by impairing activation mediated by thrombin and plasmin; however, it does not block the stronger activator, thrombin/thrombomodulin. 17 Interestingly this antibody also prevents the specific interaction of TAFIa on fibrin, but not on the other small proinflammatory substrates The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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• Early thrombolytic treatment with a bispecific inhibitor against TAFI and PAI-1 is effective without exogenous tPA.• Even at the highest dose tested, the bispecific inhibitor against TAFI and PAI-1 does not prolong bleeding time.Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissuetype plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. (Blood. 2015;125(8):1325-1332 IntroductionPlasminogen activators are the only thrombolytic agents approved to rapidly revascularize a thrombosed vessel. Reperfusion of the ischemiaaffected organ leads to an improved outcome in patients when applied within the first hours after ischemic onset.1 Despite this evidence-based beneficial effect, current thrombolytic agents remain widely underutilized due to life-threatening side effects such as cerebral hemorrhages and possible neurotoxicity.2,3 For acute ischemic stroke, in particular, the only licensed treatment option consists of a high systemic dose of recombinant tissue-type plasminogen activator (tPA), which is actually given to ,10% of the patients. Therefore, there is an unmet clinical need to explore novel therapeutic avenues to enhance fibrinolysis without plasminogen activator-associated adverse effects. Endogenous intravascular fibrinolysis is driven on the release of tPA from the endothelium, which in turn enzymatically activates plasminogen into the fibrin-degrading enzyme, plasmin.4 This activation step is attenuated by circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). Activated TAFI (TAFIa; encoded by the CPB2 gene) eliminates C-terminal Lys exposed on partially degraded fibrin, which ultimately leads to a diminished efficiency and localizati...

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Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Cited by 30 publications

References 32 publications

Effect of Reteplase™ and PAI-1 antibodies on postoperative adhesion formation in a laparoscopic mouse model

Effect of Reteplase™ and PAI-1 antibodies on postoperative adhesion formation in a laparoscopic mouse model

Plasminogen activator inhibitor-1 modulates adipocyte differentiation

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

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