ACT001 improved cardiovascular function in septic mice by inhibiting the production of proinflammatory cytokines and the expression of JAK-STAT signaling pathway

Zhen Peng; Xiaolong Lv; Xintong Wang; Ting Shang; Jing Chang; Khalid Salahdiin; Yue Guo; Zhisen Zhang; Ru Shen; Ming Lyu; Shuang He; Jian Yang; Yuefei Wang; Xiumei Gao; Yan Zhu; Yuxin Feng

doi:10.3389/fphar.2023.1265177

ACT001 improved cardiovascular function in septic mice by inhibiting the production of proinflammatory cytokines and the expression of JAK-STAT signaling pathway

Front Pharmacol. 2023 Nov 29:14:1265177. doi: 10.3389/fphar.2023.1265177. eCollection 2023.

Authors

Zhen Peng^#^{1

2}, Xiaolong Lv^#^{1

2}, Xintong Wang^#^{1

2}, Ting Shang^{1

2}, Jing Chang^{1

2}, Khalid Salahdiin^{1

2}, Yue Guo^{1

2}, Zhisen Zhang^{1

2}, Ru Shen^{1

2}, Ming Lyu^{1

2}, Shuang He^{1

2}, Jian Yang^{1

2}, Yuefei Wang¹, Xiumei Gao¹, Yan Zhu^{1

2}, Yuxin Feng^{1

2}

Affiliations

¹ State Key Laboratory of Component-based Chinese Medicine, Tuanbo New Town, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
² Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin Economic Developing Area, Tianjin, China.

^# Contributed equally.

Abstract

Sepsis is a life-threatening multiple organ dysfunction syndrome (MODS) caused by a microbial infection that leads to high morbidity and mortality worldwide. Sepsis-induced cardiomyopathy (SIC) and coagulopathy promote the progression of adverse outcomes in sepsis. Here, we reported that ACT001, a modified compound of parthenolide, improved the survival of sepsis mice. In this work, we used cecal ligation and puncture (CLP) model to induce SIC. Transthoracic echocardiography and HE staining assays were adopted to evaluate the influence of ACT001 on sepsis-induced cardiac dysfunction. Our results showed that ACT001 significantly improved heart function and reduced SIC. Coagulation accelerates organ damage in sepsis. We found that ACT001 decreased blood clotting in the FeCl₃-induced carotid artery thrombosis experiment. ACT001 also reduced the production of neutrophil extracellular traps (NETs). RNA-sequencing of heart tissues revealed that ACT001 significantly downregulated the expression of pro-inflammatory cytokines and the JAK-STAT signaling pathway. These results were confirmed with real-time PCR and ELISA. In summary, we found ACT001 rescued mice from septic shock by protecting the cardiovascular system. This was partially mediated by inhibiting pro-inflammatory cytokine production and down-regulating the JAK-STAT signaling.

Keywords: ACT001; JAK-STAT signaling pathway; cecal ligation and puncture; coagulation; sepsis-induced cardiomyopathy; septic shock.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This project was supported by the National Natural Science Foundation of China (Nos: 81774018, 81973581, and 81873037); Tianjin Municipal Education Commission (Grant Number: TD13-5046); Tianjin Municipal Science and Technology Bureau (No. 20ZY JDJC00070).