Abstract
Heart aging is characterized by structural and diastolic dysfunction of the heart. However, there is still no effective drug to prevent and treat the abnormal changes in cardiac function caused by aging. Here, we present the preventive effects of emodin and its derivative Kanglexin (KLX) against heart aging. We found that the diastolic dysfunction and cardiac remodeling in mice with D-galactose (D-gal)-induced aging were markedly mitigated by KLX and emodin. In addition, the senescence of neonatal mouse cardiomyocytes induced by D-gal was also reversed by KLX and emodin treatment. However, KLX exhibited better anti-heart aging effects than emodin at the same dose. Dysregulated mitophagy was observed in aging hearts and in senescent neonatal mouse cardiomyocytes, and KLX produced a greater increase in mitophagy than emodin. The mitophagy-promoting effects of KLX and emodin were ascribed to their abilities to enhance the protein stability of Parkin, a key modulator in mitophagy, with different potencies. Molecular docking and SPR analysis demonstrated that KLX has a higher affinity for the ubiquitin-like (UBL) domain of Parkin than emodin. The UBL domain might contribute to the stabilizing effects of KLX on Parkin. In conclusion, this study identifies KLX and emodin as effective anti-heart aging drugs that activate Parkin-mediated mitophagy and outlines their putative therapeutic importance.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81773735, 81903610, 91949130, 81961138018, and 81730012) and the National Key R&D Program of China (2017YFC1702003).
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BFY and YZ conceived and designed the study and wrote the paper. HML, XL and ZYM performed major experiments and analyzed the data. LW, LMZ, HC, ZXW, and XQT performed Western blotting, immunochemistry and qPCR experiments. HC, XHL, and XB performed primary cell culture and transfection experiments. YL, WNH, and HL performed animal experiments. All authors contributed to and approved the manuscript.
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Li, Hm., Liu, X., Meng, Zy. et al. Kanglexin delays heart aging by promoting mitophagy. Acta Pharmacol Sin 43, 613–623 (2022). https://doi.org/10.1038/s41401-021-00686-5
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DOI: https://doi.org/10.1038/s41401-021-00686-5
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