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

鞘氨醇-1-磷酸(S1P)是一种具有多种心血管功能的生物活性鞘磷脂。其作用由5种受体亚型(S1PR1-5)及其偶联的异源三聚体G蛋白介导。临床上，S1PR调节剂fingolimod、ozAnimod、siponimod或ponesimod用于治疗各种形式的多发性硬化症。在动物研究中，我们和其他人已经证明，S1P本身是一个有希望的药物治疗急性心肌梗死(AMI)的靶点，因为它在许多小鼠和大型动物模型中显著减少了梗塞面积。然而，其在缺血前的成功应用并不能满足临床情况的要求，在临床情况下，只有在接触医生或血运重建期间才能给药。在初步应用中，我们首次证明了S1P对急性心肌梗死后心脏重构的积极影响与初始梗死面积无关：给予S1P降解抑制剂4-脱氧吡哆醇(4-deoxypyridoxine，DOP)并未如预期的那样改变无复流性心肌梗死模型的心肌梗死面积，但显著改善了重构，使瘢痕更小，心功能更好。心肌细胞S1PR1在这方面发挥了重要作用，这在组织特异性基因敲除小鼠中得到了证实。然而，S1PR3也发挥了相关的作用，因为它的缺失限制了无再流性急性心肌梗死后的心肌愈合。最后，我们在心脏缺血/再灌注模型中测试了再灌注24小时后应用DOP的临床现实情景，观察到心功能得到改善，瘢痕也变小。这为临床上相关的S1PR调节剂作为一种辅助治疗来优化急性心肌梗死后的在体重构提供了原则性实验和实验模型的证据。因此，本项目的目的是：(I)研究S1PR调节剂对小鼠在体急性心肌梗死后重塑的影响；(Ii)确定相关的受体、细胞类型和机制；(Iii)在朗恩多夫模型中对接受血浆S1PR调节剂治疗的患者的心脏保护效果进行翻译转移研究，并应用鞘磷脂组学方法确定他们的代谢作用谱和任何新的生物活性脂类。在该项目结束时，将清楚地展示哪种S1P途径的调节剂或哪种联合疗法提供了一种有希望的方法来改善急性心肌梗死后的心功能，为潜在的临床应用铺平了道路。

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.