Phosphorylation of Vasodilator-Stimulated Phosphoprotein Prevents Platelet-Neutrophil Complex Formation and Dampens Myocardial Ischemia-Reperfusion Injury

Köhler, David; Straub, Andreas; Weissmüller, Thomas; Faigle, Marion; Bender, Sarah; Lehmann, Rainer; Wendel, Hans-Peter; Kurz, Julia; Walter, Ulrich; Zacharowski, Kai; Rosenberger, Peter

doi:10.1161/circulationaha.110.014555

Cited by 54 publications

(63 citation statements)

References 43 publications

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“…Aggregate formation was then induced by adding fMLP (10 mM), 2MeSADP (100 nM), or PAF (10 nM) and incubated for a further 20 minutes at 25°C. The reaction was stopped by adding 2% paraformaldehyde solution in PBS and samples were kept at 4°C until analysis (Rinder et al, 1991;Köhler et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

Prasugrel Metabolites Inhibit Neutrophil Functions

Liverani

Rico

Garcia

et al. 2012

J Pharmacol Exp Ther

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Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y 12 receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucylphenylalanine (fMLP)-and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP-or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y 12 and P2Y 13 receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their antiinflammatory effects previously observed. However, these metabolites do not act through either the P2Y 12 or P2Y 13 receptor in neutrophils.

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Section: Methodsmentioning

confidence: 99%

Prasugrel Metabolites Inhibit Neutrophil Functions

Liverani

Rico

Garcia

et al. 2012

J Pharmacol Exp Ther

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“…These observations may help explain the importance of platelets in promoting leukocyte infiltration into ischemic tissues. 9,32,33 The needle injury model used in this study produces localized injury to endothelial cells that is sufficient to induce a localized and persistent thrombotic response. Although the details of this injury model will be published elsewhere, we found that needle injury does not lead to loss of endothelial cells, but rather to perturbation of their normal antithrombotic function, leading to a-thrombin generation and rapid platelet activation.…”

Section: Blood 30 May 2013 X Volume 121 Number 22 Leukocyte Migratimentioning

confidence: 99%

The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi

Ghasemzadeh

Kaplan

Alwis

et al. 2013

Blood

120

118

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“…[1][2][3] Platelet inhibition is a key factor in the management of acute myocardial infarction (AMI), and increasingly potent antiplatelet drugs targeting the platelet ADP receptor P2Y 12 have improved patient outcome. 4,5 In addition, the amount of platelets in the ischemic/reperfused myocardium has an important prognostic value.…”

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confidence: 99%

Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging

et al. 2014

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Background-Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion. Methods and Results-Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y 12 −/− mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y 12 −/− mice. Conclusions-Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury. (Circulation. 2014;130:676-687.)

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Phosphorylation of Vasodilator-Stimulated Phosphoprotein Prevents Platelet-Neutrophil Complex Formation and Dampens Myocardial Ischemia-Reperfusion Injury

Abstract: Previously unappreciated, the phosphorylation of VASP performs a key function for the formation of PNCs that is crucially important for the extent of myocardial IR injury.

Cited by 54 publications

References 43 publications

Prasugrel Metabolites Inhibit Neutrophil Functions

Prasugrel Metabolites Inhibit Neutrophil Functions

The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi

Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging

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