Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction

Amin Polzin, Lisa Dannenberg, Marcel Benkhoff, Maike Barcik, Carolin Helten, Philipp Mourikis, Samantha Ahlbrecht, Laura Wildeis, Justus Ziese, Dorothee Zikeli, Daniel Metzen, Hao Hu, Leonard Baensch, Nathalie H. Schröder, Petra Keul, Sarah Weske, Philipp Wollnitzke, Dragos Duse, Süreyya Saffak, Mareike Cramer, Florian Bönner, Tina Müller, Markus H. Gräler, Tobias Zeus, Malte Kelm and Bodo Levkau ()
Additional contact information
Amin Polzin: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Lisa Dannenberg: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Marcel Benkhoff: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Maike Barcik: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Carolin Helten: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Philipp Mourikis: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Samantha Ahlbrecht: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Laura Wildeis: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Justus Ziese: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Dorothee Zikeli: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Daniel Metzen: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Hao Hu: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Leonard Baensch: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Nathalie H. Schröder: University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Petra Keul: University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Sarah Weske: University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Philipp Wollnitzke: University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Dragos Duse: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Süreyya Saffak: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Mareike Cramer: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Florian Bönner: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Tina Müller: University Hospital Jena
Markus H. Gräler: University Hospital Jena
Tobias Zeus: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Malte Kelm: University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf
Bodo Levkau: University Hospital Düsseldorf, Heinrich Heine University Düsseldorf

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Antiplatelet medication is standard of care in acute myocardial infarction (AMI). However, it may have obscured beneficial properties of the activated platelet secretome. We identify platelets as major source of a sphingosine-1-phosphate (S1P) burst during AMI, and find its magnitude to favorably associate with cardiovascular mortality and infarct size in STEMI patients over 12 months. Experimentally, administration of supernatant from activated platelets reduces infarct size in murine AMI, which is blunted in platelets deficient for S1P export (Mfsd2b) or production (Sphk1) and in mice deficient for cardiomyocyte S1P receptor 1 (S1P1). Our study reveals an exploitable therapeutic window in antiplatelet therapy in AMI as the GPIIb/IIIa antagonist tirofiban preserves S1P release and cardioprotection, whereas the P2Y12 antagonist cangrelor does not. Here, we report that platelet-mediated intrinsic cardioprotection is an exciting therapeutic paradigm reaching beyond AMI, the benefits of which may need to be considered in all antiplatelet therapies.

Date: 2023
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DOI: 10.1038/s41467-023-38069-5

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