Qingre Huoxue Decoction Alleviates Atherosclerosis by Regulating Macrophage Polarization Through Exosomal miR-26a-5p.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-12-28 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S487476

Weifeng He, Huanyi Zhao, Weiqi Xue, Yuan Luo, Mengyuan Yan, Junlong Li, Lijin Qing, Wei Wu, Zheng Jin

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Abstract

Background: Qingre Huoxue Decoction (QRHX) is a classical Chinese herbal prescription widely used in clinical practice for the treatment of atherosclerosis (AS). Our previous study demonstrated its efficacy in stabilizing plaque and improving prognosis, as well as its ability to regulate macrophage polarization. This study aimed to further investigate the effects of QRHX on AS and explore the underlying mechanisms.

Methods: ApoE^-/- mice were fed a high-fat diet (HFD) for 8 weeks in order to establish an AS model. Oil Red O, H&E, Masson, and IHC staining were employed to assess lipid accumulation, plaque development, collagen loss and target of the aortas tissue. ELISA was employed to measure the levels of TNF-α and IL-10 in serum. Dual luciferase reporter assay was conducted to ascertain the connection between miR-26a-5p and PTGS2 in vitro. Western blot and RT-qPCR assay were conducted to assess the NF-κB signaling pathway and macrophage polarization. The effects of miR-26a-5p were tested after transfecting miR-26a-5p over-expressive lentivirus.

Results: QRHX attenuated HFD-induced plaque progression and inflammation of AS model mice. BMDM-derived exosomes (BMDM-exo) increased miR-26a-5p and decreased PTGS2 expressions, inhibited the NF-κB signaling pathway and regulated macrophage polarization in vivo. These effects of BMDM-exo were further enhanced after QRHX intervention. Dual luciferase reporter assay results showed that miR-26a-5p directly binds to the 3'-UTR of PTGS2 mRNA and regulates the expression of PTGS2. The miR-26a-5p of BMDM-exo played a key role in macrophage polarization. After overexpression of miR-26a-5p, the NF-κB signaling pathway was inhibited and macrophages were converted from M1 to M2 in vitro.

Conclusion: QRHX can exert anti-inflammatory and plaque-stabilizing effects through exosomal miR-26a-5p via inhibiting the PTGS2/NF-κB signaling pathway and regulating macrophage phenotype from M1 to M2 polarization in AS.

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清热活血汤通过外泌体miR-26a-5p调节巨噬细胞极化减轻动脉粥样硬化

背景：清热化痰汤（QRHX）是临床上广泛用于治疗动脉粥样硬化（AS）的经典中药处方。我们之前的研究证明了它在稳定斑块和改善预后方面的疗效，以及它调节巨噬细胞极化的能力。本研究旨在进一步研究QRHX对AS的影响并探索其潜在机制：方法：将载脂蛋白E-/-小鼠饲喂高脂饮食（HFD）8周，以建立强直性脊柱炎模型。采用油红 O、H&E、Masson 和 IHC 染色法评估主动脉组织的脂质积累、斑块发展、胶原流失和靶点。采用酶联免疫吸附法测定血清中 TNF-α 和 IL-10 的水平。为了确定 miR-26a-5p 和 PTGS2 在体外的联系，进行了双荧光素酶报告实验。通过 Western 印迹和 RT-qPCR 检测来评估 NF-κB 信号通路和巨噬细胞极化。转染miR-26a-5p过表达慢病毒后，检测了miR-26a-5p的作用：结果：QRHX减轻了HFD诱导的AS模型小鼠斑块进展和炎症。BMDM衍生的外泌体（BMDM-exo）增加了miR-26a-5p的表达，降低了PTGS2的表达，抑制了NF-κB信号通路，调节了体内巨噬细胞的极化。QRHX 干预后，BMDM-exo 的这些作用进一步增强。双荧光素酶报告实验结果表明，miR-26a-5p直接与PTGS2 mRNA的3'-UTR结合并调控PTGS2的表达。BMDM-exo的miR-26a-5p在巨噬细胞极化过程中发挥了关键作用。过表达 miR-26a-5p 后，NF-κB 信号通路受到抑制，巨噬细胞在体外由 M1 转为 M2：结论：QRHX可通过抑制PTGS2/NF-κB信号通路，调节AS中巨噬细胞表型从M1向M2极化转变，从而通过外泌体miR-26a-5p发挥抗炎和稳定斑块的作用。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.