Institute for Translational Pharmacology Düsseldorf, Medical Faculty, University Hospital of the Heinrich Heine University, Universitätsstr. 1, 40225, Düsseldorf, Germany.
Department of Cardiothoracic Surgery, Heart Center of the University Hospital of Cologne, Cologne, Germany.
Basic Res Cardiol. 2023 Aug 14;118(1):31. doi: 10.1007/s00395-023-01001-5.
Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.
利伐沙班通过抑制因子 Xa 已被证明具有心脏保护作用，常用于治疗心房颤动等疾病。利伐沙班的抗炎作用众所周知，但潜在机制仍不完全清楚。迄今为止，尽管越来越多的证据表明骨髓及其激活在心血管疾病的发展/进展中具有重要意义，但尚无研究关注利伐沙班对骨髓的影响。因此，我们研究了利伐沙班在稳态条件下和应对重大心血管事件时对骨髓组成的影响。利伐沙班治疗小鼠 7 天可明显减少骨髓中成熟的白细胞。尽管骨髓源性成熟髓样白细胞的凋亡不受影响，但谱系阴性骨髓细胞在粒细胞-单核细胞祖细胞水平上表现出分化停滞，特别是通过下调转录因子 Spi1 和 Csfr1 影响中性粒细胞的成熟。为了评估这种情况是否也存在于白细胞需求增加的情况下，我们使小鼠发生心肌缺血/再灌注损伤（I/R）：用利伐沙班预处理 7 天导致 I/R 后 72 小时心脏炎症减少和循环白细胞数量降低。然而，骨髓造血显示出对白细胞分化停滞的挽救，表明利伐沙班的抑制作用仅限于稳态条件，并且在紧急造血过程中主要被消除。在翻译中，接受利伐沙班治疗的 ST 段抬高型心肌梗死患者也表现出循环白细胞数量减少。总之，我们证明利伐沙班可减弱骨髓中的中性粒细胞成熟，这可能为限制 I/R 后免疫反应过度提供一种治疗选择。
