Chlorogenic acid and ferulic acid in SMYAD alleviate diabetic cardiomyopathy by inhibiting cardiac lipotoxicity via GCGR/PPARα and GCGR/AMPK pathways

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-24 DOI:10.1016/j.phymed.2025.156906

Lin Li , Kai Huang , Dong Wang , Deshuang Yang , Kuo Gao , Jiayang Tang , Xiaoqi Wei , Haiyin Pu , Jiang Yu , Dongwei Zhang , Shuzhen Guo

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引用次数: 0

Abstract

Background

Diabetic cardiomyopathy (DCM) causes a high risk of heart failure, necessitating effective therapies. The Si-Miao-Yong-An decoction (SMYAD) has been widely applied in the clinical management of diabetes mellitus and cardiovascular diseases within the paradigm of traditional Chinese medicine (TCM), but its active constituents and mechanism of the action against DCM are poorly understood.

Purpose

The aim of this study was to evaluate the effects of chlorogenic acid (CGA) and ferulic acid (FA), the main active ingredients of SMYAD, on cardiac function and cardiac lipotoxicity in mice with DCM, as well as to investigate their potential molecular mechanisms.

Methods

The cardioprotective effects of CGA and FA on DCM mice were identified by echocardiography, HE, Masson, and Oil Red O. Immunofluorescence, flow cytometry, MitoTracker Green staining, and seahorse analysis were used to study the effects of CGA and FA on palmitic acid (PA)-induced lipotoxicity in cardiomyocytes. Finally, the regulatory effects of CGA and FA on GCGR/PPARα and GCGR/AMPK signalling pathways were detected by Ad GCGR-infection, molecular docking, RT-PCR and western blot.

Results

Based on previously identified 20 representative blood prototype components and in vitro multilayer lipid toxicity analysis, chlorogenic acid (CGA) and ferulic acid (FA) were screened as the main active components of SMYAD against DCM. In vivo experiments showed that CGA and FA attenuated lipotoxicity associated with cardiac GLC/GCGR in DCM mice, thereby protecting cardiac function. In vitro results showed that GCGR inhibitor (Adomeglivant) reduces PA-induced apoptosis, indicating that PA leads to cardiomyocyte lipotoxic apoptosis by activating GCGR. Moreover, CGA and FA inhibit PA-induced cardiomyocyte lipotoxic apoptosis, mitochondrial dysfunction, and energy substrate transition through inhibiting GCGR/PPARα and GCGR/AMPK pathways. Furthermore, GLC-stimulated/GCGR-infected H9c2 cardiomyocyte lipotoxic apoptosis and downstream proteins were effectively suppressed by CGA and FA, which is consistent with the effect of Adomeglivant. Docking results showed that ASP1018 and THR1024 of GCGR are the principal molecular targets for both CGA and FA.

Conclusion

GLC lipotoxic signaling is a crucial target in mediating cardiac lipotoxicity development. CGA and FA could inhibit DCM by regulating the GCGR/PPARα and GCGR/AMPK pathway, offering a novel strategy for the development of anti-DCM drugs.

查看原文本刊更多论文

SMYAD中的绿原酸和阿威酸通过GCGR/PPARα和GCGR/AMPK途径抑制心脏脂肪毒性，减轻糖尿病心肌病

背景：糖尿病性心肌病（DCM）引起心力衰竭的高风险，需要有效的治疗。四苗永安汤（SMYAD）在中医模式下被广泛应用于糖尿病和心血管疾病的临床治疗，但其抗DCM的有效成分和作用机制尚不清楚。目的研究SMYAD的主要活性成分绿原酸（CGA）和阿魏酸（FA）对DCM小鼠心功能和心脏脂肪毒性的影响，并探讨其可能的分子机制。方法采用超声心动图、HE、Masson、Oil Red o检测CGA和FA对DCM小鼠的心脏保护作用。采用免疫荧光、流式细胞术、MitoTracker Green染色、海马分析等方法研究CGA和FA对棕榈酸（PA）诱导的心肌细胞脂毒性的影响。最后，通过Ad - GCGR感染、分子对接、RT-PCR和western blot检测CGA和FA对GCGR/PPARα和GCGR/AMPK信号通路的调控作用。结果基于已鉴定的20种具有代表性的血液原型成分和体外多层脂质毒性分析，筛选出绿原酸（CGA）和阿魏酸（FA）为SMYAD抗DCM的主要活性成分。体内实验表明，CGA和FA可减轻DCM小鼠心脏GLC/GCGR相关的脂肪毒性，从而保护心功能。体外实验结果显示，GCGR抑制剂adomegliant可减轻PA诱导的心肌细胞凋亡，提示PA通过激活GCGR导致心肌细胞脂毒性凋亡。此外，CGA和FA通过抑制GCGR/PPARα和GCGR/AMPK途径抑制pa诱导的心肌细胞脂毒性凋亡、线粒体功能障碍和能量底物转移。此外，glc刺激/ gcgr感染的H9c2心肌细胞脂毒性凋亡和下游蛋白被CGA和FA有效抑制，这与adomegliant的作用一致。对接结果显示，GCGR的ASP1018和THR1024是CGA和FA的主要分子靶点。结论lc脂毒性信号是介导心脏脂毒性发展的重要靶点。CGA和FA可通过调控GCGR/PPARα和GCGR/AMPK通路抑制DCM，为开发抗DCM药物提供了新的策略。

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.