Skip to main content

ORIGINAL RESEARCH article

Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
Volume 12 - 2024 | doi: 10.3389/fcell.2024.1510232
This article is part of the Research Topic Ferroptosis and Cuproptosis: Unveiling Pathways and Translational Prospects View all 3 articles

Ferrostatin-1 Improves Acute Sepsis-induced Cardiomyopathy via Inhibiting Neutrophil Infiltration through Impaired Chemokine Axis

Provisionally accepted
Jialin Li Jialin Li Fang Xiao Fang Xiao Bingsen Lin Bingsen Lin Zhilei Huang Zhilei Huang Mingyue Wu Mingyue Wu Huan Ma Huan Ma Ruoxu Dou Ruoxu Dou Xiaodong Song Xiaodong Song Zhongxing Wang Zhongxing Wang Changjie Cai Changjie Cai Xiangdong Guan Xiangdong Guan Jie Xu Jie Xu *Fu-Li Xiang Fu-Li Xiang *
  • Sun Yat-sen University, Guangzhou, China

The final, formatted version of the article will be published soon.

    Sepsis-induced cardiomyopathy is a common complication of sepsis and is associated with higher mortality. To date, effective diagnostic and management strategies are still lacking. Recent studies suggest that ferroptosis plays a critical role in sepsis-induced cardiomyopathy and ferroptosis inhibitor Ferrostatin-1 (Fer-1) improved cardiac dysfunction and survival in lipopolysaccharide (LPS) induced endotoxemia. However, the effects of Fer-1 in cardiac dysfunction in the early stages of cecal ligation and puncture (CLP) induced sepsis remains unclear. Our study aims to elucidate the role of Fer-1 in the acute phase of peritonitis sepsis induced cardiac injury. CLP was used to induce peritonitis sepsis in mice. Pretreatment of ferroptosis inhibitor ferrostatin-1 (Fer-1) was used in the in vivo models. Survival was monitored for 48h. Cardiac function and histology were analyzed 6h after surgery. We found that ejection fraction (EF) remained normal at 6h after CLP, but the contractility detected by cardiac muscle strain analysis was significantly reduced, along with increased immune cell infiltration. Pretreating the CLP mice with 5 mg/kg Fer-1 significantly reduced mortality. At 6h after CLP, ferroptosis key regulator Gpx4, cardiac iron and malonaldehyde (MDA) did not change, but ferroptosis marker gene expression increased. Fer-1 treatment showed beneficial effects in cardiac function, less myocardial inflammatory cytokine expression and significantly inhibited immune cells, especially neutrophil infiltration in the heart. Consistently, expression of neutrophil associated chemokines (Ccrl2, Cxcl2, Cxcl3 and Cxcl5) as well as extracellular matrix (ECM) degradation enzymes (Adamts1, Adamts4, Adamts9 and Mmp8) significantly decreased in Fer-1 pre-treated CLP heart. Our findings suggest that Fer-1 inhibits neutrophil infiltration in early sepsis by disrupting the chemokine axis, highlighting its potential as a therapeutic option to manage acute immune overactivation in early stages of sepsis-induced cardiomyopathy.

    Keywords: Sepsis-induced cardiomyopathy, Ferrostatin-1(Fer-1), Neutrophil, chemokine, ferroptosis

    Received: 12 Oct 2024; Accepted: 29 Nov 2024.

    Copyright: © 2024 Li, Xiao, Lin, Huang, Wu, Ma, Dou, Song, Wang, Cai, Guan, Xu and Xiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Jie Xu, Sun Yat-sen University, Guangzhou, China
    Fu-Li Xiang, Sun Yat-sen University, Guangzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.