Celastrol exerts antiarrhythmic effects in chronic heart failure via NLRP3/Caspase-1/IL-1β signaling pathway

Wuping Tan; Siyi Cheng; Qinfang Qiu; Jiaxing Huang; Mengjie Xie; Lingpeng Song; Zhen Zhou; Yijun Wang; Fuding Guo; Xiaoxing Jin; Zeyan Li; Xiao Xu; Hong Jiang; Xiaoya Zhou

doi:10.1016/j.biopha.2024.117121

Celastrol exerts antiarrhythmic effects in chronic heart failure via NLRP3/Caspase-1/IL-1β signaling pathway

Biomed Pharmacother. 2024 Aug:177:117121. doi: 10.1016/j.biopha.2024.117121. Epub 2024 Jul 14.

Authors

Wuping Tan¹, Siyi Cheng¹, Qinfang Qiu¹, Jiaxing Huang¹, Mengjie Xie¹, Lingpeng Song¹, Zhen Zhou¹, Yijun Wang¹, Fuding Guo¹, Xiaoxing Jin¹, Zeyan Li¹, Xiao Xu¹, Hong Jiang², Xiaoya Zhou³

Affiliations

¹ Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, PR China; Cardiac Autonomic Nervous System Research Center of Wuhan University, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, PR China; Hubei Key Laboratory of Autonomic Nervous System Modulation, PR China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, PR China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China.
² Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, PR China; Cardiac Autonomic Nervous System Research Center of Wuhan University, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, PR China; Hubei Key Laboratory of Autonomic Nervous System Modulation, PR China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, PR China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China. Electronic address: hong-jiang@whu.edu.cn.
³ Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, PR China; Cardiac Autonomic Nervous System Research Center of Wuhan University, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, PR China; Hubei Key Laboratory of Autonomic Nervous System Modulation, PR China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, PR China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China. Electronic address: whuzhouxiaoya@whu.edu.cn.

PMID: 39002443
DOI: 10.1016/j.biopha.2024.117121

Abstract

Objectives: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI.

Methods: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome.

Results: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway.

Conclusions: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1β pathway.

Keywords: Autonomic nerve remodeling; Celastrol; Myocardial infarction; Ventricular arrhythmias; Ventricular electrical remodeling.

MeSH terms

Animals
Anti-Arrhythmia Agents* / pharmacology
Arrhythmias, Cardiac* / drug therapy
Caspase 1* / metabolism
Cell Line
Chronic Disease
Disease Models, Animal
Heart Failure* / drug therapy
Heart Failure* / metabolism
Heart Failure* / physiopathology
Heart Rate / drug effects
Inflammasomes / drug effects
Inflammasomes / metabolism
Interleukin-1beta* / metabolism
Male
Myocardial Infarction* / drug therapy
Myocardial Infarction* / metabolism
Myocardial Infarction* / pathology
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Pentacyclic Triterpenes* / pharmacology
Rats
Rats, Sprague-Dawley*
Signal Transduction* / drug effects
Triterpenes / pharmacology

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
celastrol
Pentacyclic Triterpenes
Caspase 1
Anti-Arrhythmia Agents
Nlrp3 protein, rat
Interleukin-1beta
Triterpenes
Inflammasomes
IL1B protein, rat