基于Ruxolitinib的衰老疗法通过抑制JAK2/STAT3信号通路减轻脓毒症心肌病中心肌细胞的衰老。

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-08-12 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.96489
Boshen Yang, Taixi Li, Zhixiang Wang, Yuankang Zhu, Kaifan Niu, Sien Hu, Zhiqi Lin, Xinjie Zheng, Xian Jin, Chengxing Shen
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引用次数: 0

摘要

背景:细胞衰老已成为心血管研究的一个关键焦点。本研究调查了细胞衰老在脓毒性心肌病(SCM)中之前未被发现的作用,并评估了使用芦可利替尼(Ruxolitinib,Rux)作为潜在治疗方案的衰老疗法。研究方法我们采用脂多糖(LPS)诱导的新生大鼠心肌细胞(NRCMs)和两种小鼠模型--LPS诱导和盲肠结扎穿刺(CLP)诱导的SCM模型--来评估Rux的作用。利用 RNA 测序、Western 印迹(WB)、定量聚合酶链反应(qPCR)、免疫荧光、免疫组织化学、衰老相关 β-半乳糖苷酶(SA-β-gal)检测等技术研究其潜在机制。结果衰老相关分泌表型(SASP)和细胞衰老标记物在 LPS 诱导的 NRCMs 和 SCM 动物模型中明显升高,SA-β-gal 试验证实了这一点。Rux 治疗可减轻体外和体内的 SASP,同时下调衰老标记物。此外,基于 Rux 的衰老疗法减轻了线粒体介导的细胞凋亡,改善了 SCM 小鼠的心脏功能,恢复了抗氧化系统的平衡,降低了活性氧(ROS)水平。Rux 治疗可恢复线粒体膜电位,减轻线粒体形态损伤,上调线粒体复合物相关基因的表达,从而增强线粒体功能。此外,Rux 还能改善单片机诱导的线粒体动态功能障碍和内质网应激。从机制上讲,Rux 在体外和体内都抑制了 JAK2-STAT3 信号的激活。值得注意的是,低剂量 Rux 和 ABT263 在缓解单核细胞增多症方面的疗效相当。结论本研究强调了细胞衰老在单核细胞增多症发病机制中的潜在意义,并建议将基于 Rux 的衰老疗法作为一种治疗单核细胞增多症的有效方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ruxolitinib-based senomorphic therapy mitigates cardiomyocyte senescence in septic cardiomyopathy by inhibiting the JAK2/STAT3 signaling pathway.

Background: Cellular senescence has emerged as a pivotal focus in cardiovascular research. This study investigates the previously unrecognized role of cellular senescence in septic cardiomyopathy (SCM) and evaluates senomorphic therapy using ruxolitinib (Rux) as a potential treatment option. Methods: We employed lipopolysaccharide (LPS)-induced neonatal rat cardiomyocytes (NRCMs) and two mouse models-LPS-induced and cecal ligation and puncture (CLP)-induced SCM models-to assess Rux's effects. RNA sequencing, western blotting (WB), quantitative polymerase chain reaction (qPCR), immunofluorescence, immunohistochemistry, senescence-associated β-galactosidase (SA-β-gal) assay, and other techniques were utilized to investigate underlying mechanisms. Results: Senescence-associated secretory phenotype (SASP) and cellular senescence markers were markedly elevated in LPS-induced NRCMs and SCM animal models, confirmed by the SA-β-gal assay. Rux treatment attenuated SASP in vitro and in vivo, alongside downregulation of senescence markers. Moreover, Rux-based senomorphic therapy mitigated mitochondrial-mediated apoptosis, improved cardiac function in SCM mice, restored the balance of antioxidant system, and reduced reactive oxygen species (ROS) levels. Rux treatment restored mitochondrial membrane potential, mitigated mitochondrial morphological damage, and upregulated mitochondrial complex-related gene expression, thereby enhancing mitochondrial function. Additionally, Rux treatment ameliorated SCM-induced mitochondrial dynamic dysfunction and endoplasmic reticulum stress. Mechanistically, Rux inhibited JAK2-STAT3 signaling activation both in vitro and in vivo. Notably, low-dose Rux and ABT263 showed comparable efficacy in mitigating SCM. Conclusions: This study highlighted the potential significance of cellular senescence in SCM pathogenesis and suggested Rux-based senomorphic therapy as a promising therapeutic approach for SCM.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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