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01.03.2018 | Original Contribution | Ausgabe 2/2018

Basic Research in Cardiology 2/2018

Phosphorylation of vasodilator-stimulated phosphoprotein contributes to myocardial ischemic preconditioning

Zeitschrift:
Basic Research in Cardiology > Ausgabe 2/2018
Autoren:
David Köhler, Sofia-Iris Bibli, Lothar P. Klammer, Judith M. Roth, Rainer Lehmann, Ingrid Fleming, Tiago F. Granja, Andreas Straub, Peter M. Benz, Peter Rosenberger
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00395-018-0667-0) contains supplementary material, which is available to authorized users.
Peter M. Benz and Peter Rosenberger have contributed equally.

Abstract

Ischemic preconditioning (IP) is a well-known strategy to protect organs against cell death following ischemia. The previous work has shown that vasodilator-stimulated phosphoprotein (VASP) is involved in cytoskeletal reorganization and that it holds significant importance for the extent of myocardial ischemia reperfusion injury. Yet, the role of VASP during myocardial IP is, to date, not known. We report here that VASP phosphorylation at serine157 and serine239 is induced during hypoxia in vitro and during IP in vivo. The preconditioning-induced VASP phosphorylation inactivates the GP IIb/IIIa integrin receptor on platelets, which results in the reduced formation of organ compromising platelet neutrophil complexes. Experiments in chimeric mice confirmed the importance of VASP phosphorylation during myocardial IP. When studying this in VASP/ animals and in an isolated heart model, we were able to confirm the important role of VASP on myocardial IP. In conclusion, we were able to show that IP-induced VASP phosphorylation in platelets is a protective mechanism against the deleterious effects of ischemia.

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Zusatzmaterial
Supplemental Fig. 1 Flow cytometric detection of the leukocyte population (upper dot plot) and platelets as well as platelet–platelet/platelet–leukocyte aggregates (lower dot plot) a) Upper dot plot: Granulocytes, monocytes, and lymphocytes are detected in specific regions. The lower dot plot indicates platelets as well as platelet/platelet–granulocyte aggregates b and c) Dilution series determines maximal possible VASP phosphorylation at site serine 153 and serine 235 using the well-known potent phosphorylating agent PGE1 (n=4 per group) in murine thrombocytes and neutrophil granulocytes. d and e) Maximal possible VASP phosphorylation at site serine 153 and serine 235 using PGE1 (n=4 per group) in murine platelets and neutrophil granulocytes based on %-gated (TIFF 729 kb)
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Supplemental Fig. 2 Negative controls for myocardial tissue stainings. (TIFF 2076 kb)
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Supplemental Fig. 3 Verification of successful generation of VASP-chimeric animals a) Western Blot analysis of chimeric mice following bone marrow transplantation demonstrating VASP expression in the myocardial tissue and blood of WT → WT transplanted animals, myeloid WT into VASP -/- animals (WT → VASP -/- ), and VASP -/- in WT animals (VASP -/- → WT), and VASP -/- → VASP -/- transplanted control animals (pooled samples of n=6/ group). (TIFF 447 kb)
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