Department of Cardiology, Pulmonary Diseases, and Vascular Medicine, Medical Faculty, CARID Cardiovascular Research Institute of Duesseldorf, Heinrich Heine University of Duesseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
Division of Cardiology, Pulmonary Diseases and Vascular Medicine, University Hospital of Duesseldorf, Düsseldorf, Germany.
ESC Heart Fail. 2023 Feb;10(1):334-341. doi: 10.1002/ehf2.14176. Epub 2022 Oct 11.
Therapeutic options targeting post-ischaemic cardiac remodelling are sparse. The bioactive sphingolipid sphingosine-1-phosphate (S1P) reduces ischaemia/reperfusion injury. However, its impact on post-ischaemic remodelling independently of its infarct size (IS)-reducing effect is yet unknown and was addressed in this study.
Acute myocardial infarction (AMI) in mice was induced by permanent ligation of the left anterior descending artery (LAD). C57Bl6 were treated with the S1P lyase inhibitor 4-deoxypyridoxine (DOP) starting 7 days prior to AMI to increase endogenous S1P concentrations. Cardiac function and myocardial healing were assessed by cardiovascular magnetic resonance imaging (cMRI), murine echocardiography, histomorphology, and gene expression analysis. DOP effects were investigated in cardiomyocyte-specific S1P receptor 1 deficient (S1PR1 Cardio Cre+) and Cre- control mice and S1P concentrations measured by LC-MS/MS. IS and cardiac function did not differ between control and DOP-treated groups on day one after LAD-ligation despite fourfold increase in plasma S1P. In contrast, cardiac function was clearly improved and myocardial scar size reduced, respectively, on Day 21 in DOP-treated mice. The latter also exhibited smaller cardiomyocyte size and reduced embryonic gene expression. The benefit of DOP treatment was abolished in S1PR1 Cardio Cre+.
S1P improves cardiac function and myocardial healing post AMI independently of initial infarct size and accomplishes this via the cardiomyocyte S1PR1. Hence, in addition to its beneficial effects on I/R injury, S1PR1 may be a promising target in post-infarction myocardial remodelling as adjunctive therapy to revascularization as well as in patients not eligible for standard interventional procedures.
针对缺血后心脏重构的治疗选择很少。生物活性鞘脂神经酰胺 1-磷酸（S1P）可减少缺血/再灌注损伤。然而，其对缺血后重构的影响，而不考虑其梗死面积（IS）减少作用，尚不清楚，本研究对此进行了探讨。
通过永久结扎左前降支（LAD）诱导小鼠急性心肌梗死（AMI）。在 AMI 前 7 天开始用 S1P 裂合酶抑制剂 4-脱氧吡啶（DOP）治疗 C57Bl6，以增加内源性 S1P 浓度。通过心血管磁共振成像（cMRI）、小鼠超声心动图、组织形态学和基因表达分析评估心脏功能和心肌愈合。在心肌细胞特异性 S1P 受体 1 缺陷（S1PR1 Cardio Cre+）和 Cre-对照小鼠中研究了 DOP 的作用，并通过 LC-MS/MS 测量 S1P 浓度。尽管血浆 S1P 增加了四倍，但在 LAD 结扎后第一天，对照组和 DOP 治疗组的 IS 和心功能没有差异。相比之下，DOP 治疗组在第 21 天的心脏功能明显改善，心肌瘢痕面积减小。后者的心肌细胞体积也较小，胚胎基因表达降低。DOP 治疗的益处在 S1PR1 Cardio Cre+中被消除。
S1P 可改善 AMI 后心脏功能和心肌愈合，而不依赖于初始梗死面积，其通过心肌细胞 S1PR1 实现。因此，除了对 I/R 损伤的有益作用外，S1PR1 可能是梗塞后心肌重构的一个有前途的靶点，作为血运重建的辅助治疗，以及在不符合标准介入治疗的患者中。
