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

鞘氨醇-1 受体调节可改善急性心肌梗死后的缺血后重塑

• 批准号: 413659045
• 负责人: Professor Dr. Bodo Levkau
• 金额: --
• 依托单位: Klinik für Kardiologie, Pneumologie und Angiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/413659045?language=en
• 关键词: Sphingosine; receptor; modulation; improves; post

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.

1-磷酸鞘氨醇（S1 P）是一种具有多种心血管功能的生物活性鞘脂。其作用由五种受体亚型（S1 PR 1 -5）及其偶联的异源三聚体G蛋白介导。临床上，S1 PR调节剂芬戈莫德、奥扎尼莫德、辛波莫德或波奈莫德用于治疗各种形式的多发性硬化。在动物研究中，我们和其他人已经表明，S1 P本身是急性心肌梗死（AMI）药物治疗的一个有前途的目标，因为它显着减少许多小鼠和大型动物模型中的梗死面积。然而，其在缺血前应用的成功并不满足临床情况的要求，其中仅在与医生接触后或在血管重建期间才能进行给药。在初步应用中，我们首次证明S1 P对AMI后的心脏重塑有积极影响，与初始梗死面积无关：如预期的那样，在无复流AMI模型中，给予4-脱氧吡哆醇（DOP）作为S1 P降解的抑制剂并没有改变梗死面积，但在瘢痕较小和心脏功能较好方面显著改善了重塑。如在组织特异性敲除小鼠中所示，在这方面起作用的是心肌细胞S1 PR 1。然而，S1 PR 3也起着相关的作用，因为它的缺乏限制了无复流AMI后的心肌愈合。最后，我们测试了在心脏缺血/再灌注模型中再灌注后24小时应用DOP的临床现实情况，并观察到心脏功能改善和瘢痕较小。 这提供了原理实验和实验模型的证据，以测试临床相关的S1 PR调节剂作为补充疗法，以优化体内AMI后的重塑。因此，该项目的目的是：（i）研究S1 PR调节剂对小鼠体内急性心肌梗塞后重塑的作用，（ii）鉴定所涉及的受体、细胞类型和机制，和（iii）对血浆S1 PR调节剂的心脏保护功效进行翻译转移研究-在Langendorff模型中治疗患者，并应用鞘脂组学来鉴定他们的代谢作用谱和任何新的生物活性脂质。在该项目结束时，将清楚地证明S1 P通路的哪些调节剂或哪些联合治疗提供了改善AMI后心脏功能的有希望的方法，为潜在的临床应用铺平了道路。