High-density Lipoprotein–based Therapy Reduces the Hemorrhagic Complications Associated With Tissue Plasminogen Activator Treatment in Experimental Stroke

Lapergue, Bertrand; Dang, Bao Quoc; Desilles, Jean‐Philippe; Ortiz-Muñoz, Guadalupe; Delbosc, Sandrine; Loyau, Stéphane; Louedec, Liliane; Couraud, Pierre‐Olivier; Mazighi, Mikaël; Michel, Jean‐Baptiste; Meilhac, Olivier; Amarenco, Pierre

doi:10.1161/strokeaha.112.667832

Cited by 33 publications

(32 citation statements)

References 51 publications

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“…The monofilament, however, blocks the whole MCA-perfused territory, which typically yields large lesions and more easily transforms into cerebral bleeding. In this model, tPA has been previously demonstrated to increase the incidence of bleeding and edema, 57 whereas the diabody in this study did not. To study the risk of systemic bleeding on traumatic injury, we performed a tail bleeding assay in which tPA and diabody were compared ( Figure 4).…”

Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paicontrasting

confidence: 60%

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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Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paicontrasting

confidence: 60%

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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“…In mouse models of stroke, HDL infusion and S1P 1 receptor activators can reduce neuronal I/R injury in animal models and in human clinical trials (8, 10, 42, 43, 47, 49, 50). Thus, ApoM-Fc–S1P may provide a novel strategy for treatment of stroke.…”

Section: Discussionmentioning

confidence: 99%

An engineered S1P chaperone attenuates hypertension and ischemic injury

et al. 2017

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Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M–containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein–coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases.

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“…The sections were stained with 2% 2, 3, 5-triphenyltetrazolium chloride (TTC) for 20 min at 37 1C (Lapergue et al, 2013). To eliminate the contribution of post-ischemic edema to the volume of injury, infarct volume measurements were corrected for swelling according to the method of Wang et al, 2010.…”

Section: Measurement Of Infarct Size and Edema Volumementioning

confidence: 99%

Hydrogen sulfide induces neuroprotection against experimental stroke in rats by down-regulation of AQP4 via activating PKC

et al. 2015

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High-density Lipoprotein–based Therapy Reduces the Hemorrhagic Complications Associated With Tissue Plasminogen Activator Treatment in Experimental Stroke

Cited by 33 publications

References 51 publications

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

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

An engineered S1P chaperone attenuates hypertension and ischemic injury

Hydrogen sulfide induces neuroprotection against experimental stroke in rats by down-regulation of AQP4 via activating PKC

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