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Madecassoside mitigates acute myocardial infarction injury by activating the PKCB/SPARC signaling pathway

Acta Pharmacologica Sinica volume 46, pages 1624–1638 (2025)Cite this article

Abstract

The current treatments and drugs of myocardial infarction (MI) remain insufficient. In recent years, natural products have garnered significant attention for their potential in treating cardiovascular diseases due to their availability and lower toxicity. Saponins, in particular, showed promising effects for cardiac protection. In this study, we investigated the therapeutic effects of the saponin compound madecassoside in the treatment of MI, and underlying molecular mechanisms. The acute MI model was established in male mice by ligation of the left anterior descending coronary artery. The mice were treated with madecassoside (20 mg· kg−1 ·d−1, i.g.) for 14 days. After sacrificing the mice, hearts were harvested for analysis. We showed that madecassoside administration significantly mitigated cardiac function decline in MI mice by promoting angiogenesis and inhibiting myocardial cell apoptosis and fibrosis. By conducting systems pharmacology and RNA sequencing, we demonstrated that madecassoside upregulated SPARC gene expression by activating protein kinase C-β (PKCB) that had a strong promoting effect on endothelial cell angiogenesis, thus playing a crucial protective role against MI. We showed that inhibition of SPARC gene significantly reduced madecassoside-stimulated migration and tube formation of endothelial cells in vitro; co-administration of the PKCB-specific inhibitor ruboxistaurin (10 mg· kg−1 ·d−1, i.g.) abolished the cardioprotective effect of madecassoside in MI mice, validating the critical role of the PKCB/SPARC signaling pathway. This study demonstrates that madecassoside regulates the PKCB/SPARC pathway, promotes the proliferation and regeneration of vascular endothelial cells, and effectively alleviates the symptoms of MI.

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Fig. 1: Madecassoside attenuated MI-induced damage to cardiac function.
Fig. 2: Madecassoside ameliorated fibrosis caused by MI.
Fig. 3: Madecassoside reduced myocardial cell apoptosis in infarcted mice.
Fig. 4: Identification of shared targets between madecassoside and acute myocardial infarction, and enrichment analysis of GO and KEGG pathways.
Fig. 5: Inhibition of PKCB suppressed madecassoside-induced endothelial cell proliferation.
Fig. 6: Gene expression changes and enrichment analysis induced by madecassoside.
Fig. 7: Inhibiting PKCB activity results in a decrease in SPARC expression, while having no significant impact on THBS4 expression.
Fig. 8: Madecassoside promotes angiogenesis by enhancing the transcription of SPARC.
Fig. 9: Ruboxistaurin attenuates the cardioprotective effects of madcassoside in the treatment of MI.

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Acknowledgements

This study was supported by Innovative Research Group Project of the National Natural Science Foundation of China (82121001); National Natural Science Foundation of China (32200973, 82270393); Natural Science Foundation of Jiangsu Province (BK20220310 to SL).

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Authors and Affiliations

  1. Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China

    Peng Wang, Ji-qin Yang, Dan-dan Xu, Shan Lu & Yong Ji

  2. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University, Harbin, 150000, China

    Si-jia Zhang & Yong Ji

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  1. Peng Wang
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  2. Ji-qin Yang
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  3. Dan-dan Xu
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  4. Si-jia Zhang
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Contributions

SL and YJ contribute to conceptualization; PW and DDX contribute to methodology; PW contributes to software; SL, YJ, JQY, SJZ, and DDX contribute to validation; JQY contributes to formal analysis; SL, YJ, JQY, SJZ, and DDX contribute to investigation; SL and YJ contribute to resources; PW contributes to writing original draft; SL contributes to writing review and editing; PW and SL contribute to visualization; SL and YJ contribute to supervision; SL contributes to project administration; SL and YJ contribute to funding acquisition.

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Correspondence to Shan Lu or Yong Ji.

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Wang, P., Yang, Jq., Xu, Dd. et al. Madecassoside mitigates acute myocardial infarction injury by activating the PKCB/SPARC signaling pathway. Acta Pharmacol Sin 46, 1624–1638 (2025). https://doi.org/10.1038/s41401-024-01442-1

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