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GTS-21 Protected Against LPS-Induced Sepsis Myocardial Injury in Mice Through α7nAChR

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Abstract

Sepsis-induced myocardial injury is a well-known cause of mortality. The cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which the central nervous system regulates immune response through the vagus nerve and acetylcholine; the α7-nicotinic acetylcholine receptor (α7nAChR) is the main component of CHAIP; GTS-21, a synthetic α7nAChR selective agonist, has repeatedly shown its powerful anti-inflammatory effect. However, little is known about its effect on LPS-induced myocardial injury. We investigated the protective effects of GTS-21 on lipopolysaccharide (LPS)-induced cardiomyopathy via the cholinergic anti-inflammatory pathway in a mouse sepsis model. We constructed the model of myocardial injury in sepsis mice by C57BL/6 using LPS and determined the time of LPS treatment by hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). C57BL/6 mice were randomized into five groups: blank control group, model group, α-bungarotoxin + LPS group, GTS-21 + LPS group, and α-bungarotoxin + GTS-21 + LPS group. The pathological results of myocardial tissue were detected by the HE method; the apoptosis rate was detected by the TUNEL method; the relative expressions of NF-κB p65, Caspase-3, Caspase-8, Bcl-2, Bax, p53, and a7nAChR were detected by real-time quantitative PCR (RT-PCR); and the protein expressions of IL-6, IL-1 β, TNF-α, and pSTAT3 were detected by western blot. The results showed that LPS-induced myocardial pathological and apoptosis changes were significant compared with the blank group, which was reversed by GTS-21; however, pretreatment with α-bungarotoxin obviously blocked the protective effect of GTS-21. NF-κB p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1β, TNF-α, and pSTAT3 were significantly increased in the model group, while a7nAChR and Bcl-2 were significantly decreased; GTS-21 treatment reversed that result, while pretreatment with α-bungarotoxin strengthened the result in the model. And pretreatment with α-bungarotoxin blocked the protective effect of GTS-21. GTS-21 can alleviate the LPS-induced damage in the heart via a7nAChR, and pretreatment with α-bungarotoxin obviously blocked the protective effect of GTS-21 on sepsis in mice.

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Funding

This project was funded by the National Natural Science Foundation of China (No.81571871), the National Natural Science Foundation of China (No.81770276 ), the National Natural Science Foundation of China(No.81772045), Nn10 program of Harbin Medical University Cancer Hospital, Heilongjiang Health Department project (No.2017-001), Postdoctoral Funding of Heilongjiang Province (No. LBH-Z16147), and Talent Fund of Harbin Science and Technology Bureau (No.2017RAQXJ177).

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  1. Kai Kang, Kaijiang Yu and Mingyan Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Road, Harbin, 150001, China

    Weilan Kong, Kai Kang, Xianglin Meng, Yanhui Cao, Songliu Yang, Wen Liu, Jiannan Zhang & Mingyan Zhao

  2. Department of Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China

    Yang Gao

  3. Department of Critical Care Medicine, the Cancer Hospital of Harbin Medical University, 150 Haping Road, Harbin, 150081, China

    Haitao Liu & Kaijiang Yu

  4. Institute of Critical Care Medicine in Sino Russian Medical Research Center of Harbin Medical University, 150 Haping Road, Harbin, 150081, China

    Kaijiang Yu

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  1. Weilan Kong
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Correspondence to Kaijiang Yu or Mingyan Zhao.

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All experiments conformed to guidelines established by the Ministry of Health, PR China, and approved by the animal care committee of Harbin Medical University (Harbin, China).

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Kai Kang Co-first author

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Kong, W., Kang, K., Gao, Y. et al. GTS-21 Protected Against LPS-Induced Sepsis Myocardial Injury in Mice Through α7nAChR. Inflammation 41, 1073–1083 (2018). https://doi.org/10.1007/s10753-018-0759-x

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