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Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction
Amin Polzin1,2,3, Lisa Dannenberg1, Marcel Benkhoff1
1Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Insights
Platelets release sphingosine-1-phosphate (S1P) during myocardial infarction, which protects the heart. Certain antiplatelet drugs may block this benefit, suggesting a need to reconsider therapy strategies.
Area of Science:
- Cardiovascular Medicine
- Platelet Biology
- Pharmacology
Background:
- Antiplatelet therapy is standard for acute myocardial infarction (AMI).
- The beneficial roles of the activated platelet secretome may be overlooked.
- Platelets are implicated in cardiovascular disease pathogenesis and resolution.
Purpose of the Study:
- To investigate the role of platelet-derived sphingosine-1-phosphate (S1P) in acute myocardial infarction (AMI).
- To evaluate the impact of S1P on cardiovascular outcomes and infarct size in AMI patients.
- To explore the therapeutic potential of preserving S1P release during antiplatelet therapy.
Main Methods:
- Identified platelets as a primary source of S1P burst during AMI.
- Correlated S1P levels with cardiovascular mortality and infarct size in STEMI patients.
- Administered activated platelet supernatant in murine AMI models.
- Utilized genetic models deficient in S1P production/export and S1P receptor 1.
- Assessed the effect of GPIIb/IIIa and P2Y12 antagonists on S1P release and cardioprotection.
Main Results:
- Higher S1P levels favorably associated with reduced cardiovascular mortality and infarct size in STEMI patients.
- Activated platelet supernatant reduced infarct size in mice, an effect blunted by S1P pathway deficiencies.
- The GPIIb/IIIa antagonist tirofiban preserved S1P release and cardioprotection.
- The P2Y12 antagonist cangrelor did not preserve S1P release or cardioprotection.
Conclusions:
- Platelet-derived S1P mediates intrinsic cardioprotection during AMI.
- Therapeutic strategies targeting S1P may offer novel treatment avenues for AMI.
- Antiplatelet therapy requires careful consideration to avoid inhibiting beneficial S1P-mediated effects.
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.
