Naringenin exerts antiarrhythmic action in septic cardiomyopathy by downregulating the CaMKⅡ/Drp1/Bcl-2 pathway

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-20 DOI:10.1016/j.phymed.2025.157006

Yali Zhang , Yu Zhang , Hongmei Deng , Qishu Zeng , Zhu Zhu , Zhaolun Zhang , Chunyu Zhang , Minghao Li , Jianhong Li , Guang Li , Jian Feng

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Abstract

Background

Septic cardiomyopathy (SCM) is associated with sepsis and is often accompanied by progressive arrhythmia. Naringenin (Nar) is a natural dihydroflavonoid compound that plays a protective role in various cardiovascular diseases. Calcium/calmodulin-dependent kinase II (CaMKII) is a key therapeutic target in cardiac arrhythmias.

Purpose

This study investigated the effect of naringenin on arrhythmia and cardiac electrophysiology in SCM and explored the mechanism involved.

Methods

Lipopolysaccharide was used to establish SCM in a mouse model and in an H9c2 cell line. The protective role of naringenin in SCM was investigated by pretreatment with naringenin, amiodarone, and a CaMKII inhibitor (KN-93). Cardiac function, susceptibility to arrhythmia, and electrophysiological changes were assessed in the mice using echocardiography, electrocardiography, and optical mapping techniques. Network pharmacology approaches, molecular docking, and molecular dynamics simulations were used to screen for pivotal targets. The mechanism(s) underlying the protective impact of naringenin on SCM were examined in vivo, ex vivo, and in vitro.

Results

Naringenin protected against SCM by exerting anti-inflammatory effects, alleviating myocardial injury, improving cardiac dysfunction, reducing the susceptibility to arrhythmia, and stabilizing electrophysiology. Network pharmacology, molecular docking, and molecular dynamics simulations indicated that the key target protein of naringenin may be Bcl-2. Further studies confirmed that naringenin attenuated apoptosis, improved mitochondrial dysfunction, and downregulated the CaMKⅡ/Drp1/Bcl-2 pathway in SCM.

Conclusions

Naringenin attenuates the phosphorylation of Drp1 by inhibiting phosphorylation of CaMKⅡ, thereby ameliorating mitochondrial dysfunction, suppressing apoptosis, modulating myocardial electrophysiology, and ultimately reducing susceptibility to arrhythmia while improving cardiac function in SCM.

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柚皮素通过下调CaMKⅡ/Drp1/Bcl-2通路在脓毒性心肌病中发挥抗心律失常作用

背景：脓毒性心肌病（SCM）与败血症相关，常伴有进行性心律失常。柚皮素（Naringenin, Nar）是一种天然的双氢类黄酮化合物，在多种心血管疾病中起保护作用。钙/钙调素依赖性激酶II （CaMKII）是心律失常的关键治疗靶点。目的观察柚皮素对SCM患者心律失常及心电生理的影响，并探讨其作用机制。方法采用聚多糖建立小鼠模型和H9c2细胞系的SCM。通过柚皮素、胺碘酮和CaMKII抑制剂KN-93预处理，研究柚皮素对SCM的保护作用。使用超声心动图、心电图和光学测绘技术评估小鼠的心功能、心律失常易感性和电生理变化。网络药理学方法、分子对接和分子动力学模拟用于筛选关键靶点。研究了柚皮素在体内、离体和体外对SCM保护作用的机制。结果人参素具有抗炎、减轻心肌损伤、改善心功能障碍、降低心律失常易感性、稳定电生理等保护作用。网络药理学、分子对接和分子动力学模拟表明，柚皮素的关键靶蛋白可能是Bcl-2。进一步研究证实柚皮素可减轻SCM细胞凋亡，改善线粒体功能障碍，下调CaMKⅡ/Drp1/Bcl-2通路。结论snangenin通过抑制CaMKⅡ的磷酸化，减弱Drp1的磷酸化，从而改善线粒体功能障碍，抑制细胞凋亡，调节心肌电生理，最终在改善SCM心功能的同时降低心律失常易感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.