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Geniposide alleviates heart failure with preserved ejection fraction in mice by regulating cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H2O2-induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF.

GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway.

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Fig. 1: GE alleviates HFD + L-NAME-induced cardiac impairment in mice.
Fig. 2: GE alleviates HL-induced cardiac impairment in mice.
Fig. 3: GE ameliorates cardiac inflammation and apoptosis in the HFpEF mouse model.
Fig. 4: GE ameliorates cardiac fibrosis and metabolic disorders in HFpEF mice.
Fig. 5: GE alleviates oxidative stress mediated by MMP2 in HFpEF mice.
Fig. 6: GE alleviates H2O2-induced oxidative stress injury in H9c2 cells.
Fig. 7: GE-alleviated H2O2-induced oxidative stress in H9c2 cells is dependent on MMP2.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) Grant 82304503 to Shuang Zhang, Anhui Provincial Natural Science Foundation Grant 2308085QH305 to Shuang Zhang, and the Fundamental Research Funds for the Central Universities (Hefei University of Technology) grant JZ2023HGTB0288 to Shuang Zhang.

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  1. These authors contributed equally: Yan-lu Han, Teng-teng Yan

Authors and Affiliations

  1. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, 230601, China

    Yan-lu Han, Teng-teng Yan, Hua-xin Li, Sha-sha Chen, Zhen-zhen Zhang, Meng-yao Wang, Yuan-li Chen, Xiao-xiao Yang, Ling-ling Wei & Shuang Zhang

  2. Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, China

    Mei-jie Chen & Ya-jun Duan

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Contributions

YLH, SZ and YJD designed the study, drafted and edited the manuscript; YLH and TTY performed most of the experiments; HXL, SSC, ZZZ, MJC, YLC, LLW and XXY assisted with experimental protocols or data collection. MYW performed the material preparation and interpretation. All authors discussed the data and contributed to the manuscript.

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Correspondence to Shuang Zhang.

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Han, Yl., Yan, Tt., Li, Hx. et al. Geniposide alleviates heart failure with preserved ejection fraction in mice by regulating cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01341-5

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