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Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism

Abstract

Myocardial infarction (MI) causes disturbances in myocardial energy metabolism, ultimately leading to a poor prognosis. Cytosolic glycogen autophagy (glycophagy) and mitochondrial autophagy (mitophagy) are upregulated in MI to optimize energy metabolism but to a limited extent. Asiatic acid (AA), a pentacyclic triterpene derived from the traditional Chinese herb Centella asiatica, displays anti-inflammatory, antioxidant, and antiapoptotic activities. AA has been found to alleviate focal cerebral and liver ischemic injury by reversing mitochondrial dysfunction. In this study, we investigated whether AA exerted cardioprotective effects against MI by activating glycophagy and mitophagy to improve the energy balance. In vitro cardioprotective effects were examined in neonatal mouse cardiomyocytes subjected to oxygen-glucose deprivation for 12 h. Treatment with AA (2–50 μM) significantly increased cell viability and improved the energy metabolism evidenced by increased ATP level and phosphocreatine/ATP ratio. In vivo cardioprotective effects were studied in a mouse model of MI. Administration of AA (5–125 mg·kg−1·d−1, ig) significantly reduced infarct size and ischemic myocardial injury, and improved cardiac function. AA treatment also promoted mitophagy and relieved mitochondrial edema evidenced by increased number of mitophagosomes in ischemic myocardium in vivo and increased mitochondria-light chain 3 (LC3)-II colocalization in ODG-treated cardiomyocytes in vitro. Mitophagy activation was accompanied by activation of the AMPK signaling pathway. Knockdown of AMPK abolished AA-activated mitophagy. Furthermore, we showed that glycophagy was upregulated in OGD cardiomyocytes evidenced by increased starch binding domain protein 1 (STBD1)-GABA type A receptor-associated protein-like 1(GABARAPL1) interaction and extracellular acidification rate, whereas AA treatment further promoted glycophagy accompanied by PI3K/Akt activation. PI3K inhibitor LY294002 or Akt inhibitor GSK690693 blocked the effects of AA on glycophagy and glycolysis. Finally, simultaneous inhibition of glycophagy and mitophagy abolished the cardioprotective effects and energy regulation of AA. These results demonstrate that AA protects ischemic cardiomyocytes by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/Akt and AMPK pathways.

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Fig. 1: Asiatic acid (AA) protects oxygen-glucose deprivation (OGD) cardiomyocytes in vitro.
Fig. 2: AA reduces ischemic myocardial injury and improves cardiac function in vivo.
Fig. 3: AA increases ischemic cardiomyocyte mitophagy.
Fig. 4: Activation of the AMP-activated protein kinase (AMPK) signaling pathway is responsible for AA-induced mitophagy.
Fig. 5: Increased glycophagy is observed in OGD cardiomyocytes with AA treatment.
Fig. 6: Phosphoinositide 3-kinase (PI3K)/Akt is involved in AA-induced glycophagy.
Fig. 7: Glycophagy and mitophagy are critical for AA-mediated cardioprotection and energy metabolism.
Fig. 8: A proposed model for the cadioprotection of AA in MI heart and OGD cardiomyocytes.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFA0105600, 2020YFA0112600), the National Natural Sciences Foundation of China (81870208, 82070260), the Shanghai Pujiang Program (19PJ1408900), the Shanghai Animal Research Program (21140901800), the Science and Technology Development Fund of Shanghai Pudong New Area (PKJ2020-Y23), Shanghai Engineering Research Center of Artificial Heart and Heart Failure Medicine (19DZ2251000), the Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone < Stem Cell Strategic Biobank and Stem Cell Clinical Technology Transformation Platform > (ZJ2018-ZD-004), and the Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai.

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FQ analyzed the data, designed the study, and wrote the manuscript. FQ, YY, WL, and YSG performed the experiments. ZMZ, ZML, and LG provided technical support and substantial contributions to the conception and design of the study. ZML and LG directed the study, managed the project, interpreted the data, and co-wrote the manuscript.

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Correspondence to Zhong-min Liu or Ling Gao.

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Qiu, F., Yuan, Y., Luo, W. et al. Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00763-9

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Keywords

  • myocardial infarction
  • asiatic acid
  • glycophagy
  • mitophagy
  • energy metabolism
  • AMPK signaling

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