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Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics

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Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS).

Methods

Fourteen apolipoprotein E-deficient (ApoE−/−) mice were divided into 2 groups by a random number table: an AS model (ApoE−/−) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot.

Results

Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE−/− aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE−/− mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05).

Conclusion

Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.

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Author information

Authors and Affiliations

  1. The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China

    Li-qun Liu

  2. College of Integrated Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong Province, 264000, China

    Peng Zhang

  3. Health College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China

    Ying-zi Qi

  4. Department of Pharmacy, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200050, China

    Hui Li

  5. Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Yue-hua Jiang

  6. Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Chuan-hua Yang

Authors
  1. Li-qun Liu
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  2. Peng Zhang
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  4. Hui Li
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Contributions

Liu LQ performed zoology experiment, and drafted the manuscript. Zhang P performed zoology experiments and animal care. Qi YZ and Li H collected samples and analyzed data. Jang YH revised the manuscript. Yang CH designed the experiments. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Chuan-hua Yang.

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The authors declare that they have no conflicts of interest.

Additional information

Supported by Shandong Province ‘Taishan Scholar’ Construction Project Funds (No. 2018-35)

Electronic supplementary material

Appendix 1

TOP 30 Differential Metabolites in Plasma Non-targeted Metabonomics by Ultra Performance Liquid Chromatography/tandem Mass Spectrometry (UPLC-MS/MS) (n = 7, Que vs Model)

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Liu, Lq., Zhang, P., Qi, Yz. et al. Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics. Chin. J. Integr. Med. 29, 1121–1132 (2023). https://doi.org/10.1007/s11655-023-3645-9

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  • DOI: https://doi.org/10.1007/s11655-023-3645-9

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