Exploring the mechanism of Ling-Gui-Zhu-Gan decoction in metabolic cardiomyopathy via inhibiting ferroptosis.

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL
Phytomedicine Pub Date : 2024-12-01 Epub Date: 2024-11-09 DOI:10.1016/j.phymed.2024.156234
Chuan-Zhi Zhao, Hui-Min Ding, Zi-Qing Hu, Lan Zhou, Yong-Qin Du, Peng Zhou, Liang Wang
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引用次数: 0

Abstract

Objective: This study was to investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) in regulating lipid metabolism and thus inhibiting ferroptosis.

Methods: UPLC for the determination of the main chemical composition of LGZGD. A HF-induced rat model of metabolic cardiomyopathy was established. Echocardiography was used to detect cardiac function. Serum lipid levels, myocardial injury markers, and lipid peroxidation levels were detected. Pathological changes were detected. Lipid deposition was assessed by oil red O, and the mitochondrial ultrastructure was observed by electron microscopy. Mechanistically, PLIN5, CD36, ATGL, GPX4, ACSL4, FPN1, DRP1, MFF, FIS1, and OPA1 expressions were examined. After PA-induced H9c2 cells established, apoptosis, myocardial injury markers, and lipid peroxidation levels were detected and lipid deposition levels were assessed. The expressions of PLIN5, CD36, ATGL, GPX4, ACSL4 and FPN1 were detected. H9c2 cardiomyocytes with transient knockdown of PLIN5 and overexpression of PLIN5 were constructed and treated with drug administration and modeling, and the apoptosis level was detected by flow cytometry, the levels of lipid peroxidation and ROS were detected by fluorescence, and the protein and gene expressions of ACSL4 and GPX4 were detected. Results The main active components of LGZGD were liquiritin, isoliquiritin, cinnamic acid, cinnamaldehyde, glycyrrhizic acid, and atractylenolide III. LGZGD significantly improved cardiac dysfunction, lowered lipid level and lipid deposition, reduced CK, NT-proBNP and MDA levels, restored SOD levels, and improved inflammatory cell infiltration as well as collagen fiber deposition. LGZGD decreased the expression of PLIN5, CD36, ACSL4, and increased the expression of ATGL, GPX4, and FPN1. LGZGD also decreased the gene expression of DRP1, MFF, FIS1, and increased OPA1 expression. LGZGD significantly ameliorated PA-induced apoptosis, decreased lipid deposition, lowered lipid peroxidation levels and CK level, decreased PLIN5, CD36, and ACSL4 expressions, and increased ATGL, GPX4, and FPN1 expressions. LGZGD reversed cardiomyocyte injury aggravated by transient knockdown of PLIN5, decreased apoptosis levels, lipid peroxidation levels, ROS levels, and ACSL4 expressions, and increased GPX4 expression. LGZGD enhanced cardiomyocyte protection after overexpression of PLIN5, reduced apoptosis levels, lipid peroxidation level and ROS level, decreased ACSL4 expression, and increased GPX4 expression.

Conclusion: PLIN5 interferes with lipid peroxidation, regulates mitochondrial function, and inhibits HF-induced ferroptosis in cardiomyocytes. LGZGD ameliorates impairment of cardiac structural function in model rats through PLIN5-mediated ferroptosis pathway, and has the effect of preventing metabolic cardiomyopathy.

灵桂术甘汤对代谢性心肌病的抑制机制探讨
目的方法:采用UPLC法测定苓桂术甘汤的主要化学成分:方法:采用UPLC法测定苓桂术甘汤的主要化学成分。建立高频诱导的代谢性心肌病大鼠模型。采用超声心动图检测心脏功能。检测血清脂质水平、心肌损伤标志物和脂质过氧化水平。检测病理变化。用油红 O 评估脂质沉积,用电子显微镜观察线粒体超微结构。从机制上检测了 PLIN5、CD36、ATGL、GPX4、ACSL4、FPN1、DRP1、MFF、FIS1 和 OPA1 的表达。PA 诱导的 H9c2 细胞建立后,检测了细胞凋亡、心肌损伤标志物和脂质过氧化水平,并评估了脂质沉积水平。检测了 PLIN5、CD36、ATGL、GPX4、ACSL4 和 FPN1 的表达。构建瞬时敲除 PLIN5 和过表达 PLIN5 的 H9c2 心肌细胞,进行给药和建模处理,用流式细胞仪检测细胞凋亡水平,用荧光法检测脂质过氧化和 ROS 水平,检测 ACSL4 和 GPX4 的蛋白和基因表达。结果 LGZGD的主要活性成分为枸杞子苷、异枸杞子苷、肉桂酸、肉桂醛、甘草酸和白术内酯III。LGZGD 能明显改善心功能障碍,降低血脂水平和脂质沉积,降低 CK、NT-proBNP 和 MDA 水平,恢复 SOD 水平,改善炎症细胞浸润和胶原纤维沉积。LGZGD 降低了 PLIN5、CD36 和 ACSL4 的表达,增加了 ATGL、GPX4 和 FPN1 的表达。LGZGD 还降低了 DRP1、MFF、FIS1 的基因表达,增加了 OPA1 的表达。LGZGD 能明显改善 PA 诱导的细胞凋亡,减少脂质沉积,降低脂质过氧化水平和 CK 水平,减少 PLIN5、CD36 和 ACSL4 的表达,增加 ATGL、GPX4 和 FPN1 的表达。LGZGD 逆转了因瞬时敲除 PLIN5 而加重的心肌细胞损伤,降低了细胞凋亡水平、脂质过氧化水平、ROS 水平和 ACSL4 表达,并增加了 GPX4 表达。LGZGD增强了PLIN5过表达后对心肌细胞的保护,降低了细胞凋亡水平、脂质过氧化水平和ROS水平,减少了ACSL4的表达,增加了GPX4的表达:结论:PLIN5能干扰脂质过氧化,调节线粒体功能,抑制高频诱导的心肌细胞铁变态反应。LGZGD可通过PLIN5介导的铁氧化途径改善模型大鼠心脏结构功能的损伤,并具有预防代谢性心肌病的作用。
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来源期刊
Phytomedicine
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.
文献相关原料
公司名称 产品信息 采购帮参考价格
上海源叶 cinnamaldehyde
上海源叶 isoliquiritin
上海源叶 glycyrrhizic acid
上海源叶 atractylenolide III
上海源叶 Liquiritin
上海源叶 cinnamic acid
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