Huangqi-Danshen decoction improves heart failure by regulating pericardial adipose tissue derived extracellular vesicular miR-27a-3p to activate AMPKα2 mediated mitophagy

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2024-10-28 DOI:10.1016/j.phymed.2024.156187

Zhaoyang Chen , Meng Zhang , Qiyao Xu , Pengyu Lu , Min Liu , Rui Yin , Xuan Liu , Yang Dai , Xin Gao , Juexiao Gong , Sujie Zhang , Xindong Wang

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Abstract

Background

Huangqi-Danshen decoction (HDD) is a classic traditional Chinese medicine for treating heart failure. Pericardial adipose tissue (PAT) has recently gained increasing attention in cardiovascular diseases.

Purpose

This study aimed to investigate the effect of pericardial adipose tissue-derived extracellular vesicles on heart failure, the protective effect of HDD on myocardial remodel in heart failure rats, and identify the potential molecular mechanisms involved.

Methods

UPLC-MS/MS identified active components of HDD. Extracellular vesicles (EVs) from pericardial adipose tissue of sham-operated and HF rats were identified through transmission electron microscopy, nanoparticle tracking analysis and western blot. EVs were co-cultured with H9c2 cardiomyocytes in order to examine their uptake and effects. MicroRNA sequencing, dual-luciferase reporter assay and PCR were conducted for exploring specific mechanisms of EVs on hypertrophic cardiomyocytes. In vivo, heart failure was modeled in rats via transverse aortic constriction (TAC). In vitro, the hypertrophic cardiomyocyte model were established using Ang II-induced H9c2 cardiomyocytes.

Results

UPLC-MS/MS identified 11 active components in serum of HDD administrated rats. Echocardiography showed HDD improved cardiac function in TAC model rats. HE and Masson staining indicated HDD ameliorated myocardial hypertrophy and fibrosis. MicroRNA sequencing found that HDD treatment resulted in 37 differentially expressed miRNAs (DMEs) (p < 0.05 and |log₂FC| ≥ 1). KEGG analysis revealed that DEMs were enriched in the AMPK signaling pathway. PCR identified miR-27a-3p with the greatest difference in AMPK-related DMEs. Dual-luciferase reporter assay and Targetscan website were utilized to identify the target relationship between miR-27a-3p and PRKAA2 (AMPKα2). The miR-27a-3p negatively regulated AMPKα2 to inhibit mitophagy mediated by PINK1/Parkin pathway. HDD inhibited miR-27a-3p secretion from failing heart pericardial adipose tissue-derived extracellular vesicles, thereby improving inflammation, cardiac function, and myocardial remodeling through above pathways.

Conclusion

HDD inhibited the PAT-derived extracellular vesicular miR-27a-3p in failing hearts to activate AMPK/PINK1/Parkin signaling-mediated mitophagy, which improved cardiomyocyte energy metabolism, myocardial remodeling and heart failure.

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黄芪丹参汤通过调节心包脂肪组织衍生的细胞外囊泡miR-27a-3p激活AMPKα2介导的有丝分裂来改善心力衰竭。

背景：黄芪丹参汤（HDD黄芪丹参汤（HDD）是治疗心力衰竭的经典中药。目的：本研究旨在探讨心包脂肪组织衍生的细胞外囊泡对心衰的影响、HDD对心衰大鼠心肌重塑的保护作用，并确定其潜在的分子机制：UPLC-MS/MS鉴定了HDD的活性成分。方法：UPLC-MS/MS鉴定了HDD的活性成分，并通过透射电子显微镜、纳米颗粒追踪分析和Western印迹鉴定了假手术大鼠和高频大鼠心包脂肪组织中的胞外囊泡（EVs）。EVs与H9c2心肌细胞共同培养，以检测它们的吸收和作用。通过微RNA测序、双荧光素酶报告实验和聚合酶链反应，探索了EVs对肥大心肌细胞的特定作用机制。在体内，通过横向主动脉收缩（TAC）模拟大鼠心力衰竭。在体外，利用 Ang II 诱导的 H9c2 心肌细胞建立肥厚型心肌细胞模型：UPLC-MS/MS鉴定出服用HDD大鼠血清中的11种活性成分。超声心动图显示 HDD 改善了 TAC 模型大鼠的心功能。HE和Masson染色显示，HDD可改善心肌肥厚和纤维化。微RNA测序发现，HDD治疗导致37个差异表达的miRNA（DMEs）（p < 0.05且|log2FC| ≥ 1）。KEGG 分析显示，DEMs 富集于 AMPK 信号通路。PCR 鉴定出 miR-27a-3p 在 AMPK 相关 DMEs 中差异最大。利用双荧光素酶报告分析法和 Targetscan 网站确定了 miR-27a-3p 与 PRKAA2（AMPKα2）之间的靶标关系。miR-27a-3p负调控AMPKα2，从而抑制由PINK1/Parkin通路介导的有丝分裂。HDD抑制了衰竭心脏心包脂肪组织源性细胞外囊泡分泌miR-27a-3p，从而通过上述途径改善炎症、心脏功能和心肌重塑：HDD抑制了衰竭心脏中PAT衍生的细胞外囊泡miR-27a-3p，激活了AMPK/PINK1/Parkin信号介导的有丝分裂，从而改善了心肌细胞的能量代谢、心肌重塑和心力衰竭。

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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.