利伐沙班减弱骨髓生态位中性粒细胞成熟。

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
R Schneckmann, M Döring, S Gerfer, S Gorressen, S Heitmeier, C Helten, A Polzin, C Jung, M Kelm, A C Fender, U Flögel, M Grandoch
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引用次数: 0

摘要

利伐沙班对Xa因子的药理学抑制已被证明可以介导心脏保护,并经常用于心房颤动等患者。利伐沙班的抗炎作用是众所周知的,但其潜在的机制仍然不完全了解。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生/进展中具有重要意义,但尚未有研究关注利伐沙班对骨髓(BM)的影响。因此,我们研究了利伐沙班在稳态条件下和对主要心血管事件的反应中对脑内膜组成的影响。利伐沙班治疗小鼠7天后,BM中成熟白细胞明显减少。虽然BM来源的成熟髓系白细胞的凋亡不受影响,但谱系阴性BM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影响中性粒细胞成熟。为了评估这种情况是否在白细胞需求增加的情况下也持续存在,我们对小鼠进行了心脏缺血/再灌注损伤(I/R):用利伐沙班预处理7天,I/R后72小时心脏炎症减轻,循环白细胞数量降低。然而,骨髓生成显示出对白细胞分化停滞的拯救,这表明利伐沙班的抑制作用仅限于稳态条件下,主要在紧急造血时被消除。换句话说,接受利伐沙班治疗的st段抬高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以减弱脑脊髓炎中性粒细胞的成熟,这可能为限制I/R后免疫反应的过调提供了一种治疗选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.

Rivaroxaban attenuates neutrophil maturation in the bone marrow niche.

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.

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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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