Sphingosine-1-receptor modulation improves post-ischemic remodeling after acute myocardial infarction

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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid with multiple cardiovascular functions. Its effects are mediated by five receptor subtypes (S1PR1-5) and their coupled heterotrimeric G-proteins. Clinically, the S1PR modulators fingolimod, ozanimod, siponimod, or ponesimod are used in the treatment of various forms of multiple sclerosis. In animal studies, we and others have shown that S1P itself is a promising target in drug therapy for acute myocardial infarction (AMI) because it significantly reduces infarct size in many murine and large animal models. However, the success of its application pre-ischemia does not meet the requirements of the clinical situation, where administration can occur only after contact to a physician or during revascularization. In the preliminary application, we were able to demonstrate for the first time that S1P positively influenced cardiac remodeling after AMI independent of the initial infarct size: administration of 4-deoxypyridoxine (DOP) as an inhibitor of S1P degradation did not change the infarct size in the model of no-reflow AMI, as expected, but substantially improved remodeling in terms of a smaller scar and better cardiac function. Instrumental in this was cardiomyocyte S1PR1, as demonstrated in tissue-specific knockout mice. However, S1PR3 also plays a relevant role, as its absence limits myocardial healing after no-reflow AMI. Finally, we tested the clinically realistic scenario of DOP application 24 hours after reperfusion in the cardiac ischemia/reperfusion model and observed improved cardiac function and smaller scar as well. This provides the proof of principle experiments and experimental models to test clinically relevant S1PR modulators as a complementary therapy to optimize remodeling after AMI in vivo. Therefore, the aim of the project is to: (i) to investigate the effect of S1PR modulators on remodeling after acute myocardial infarction in mice in vivo, (ii) to identify the receptors, cell types, and mechanisms involved, and (iii) to perform translational transfer studies on the cardioprotective efficacy of plasma S1PR modulator-treated patients in the Langendorff model and to apply sphingolipidomics to identify their metabolic action profiles and any novel bioactive lipids. At the end of this project, it will have been clearly demonstrated which modulators of the S1P pathway or which combination therapy offer a promising approach to improve cardiac function after AMI, paving the way for potential clinical applications.