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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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1 College of Pharmacy, Harbin Medical University, Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268)
2 College of Pharmacy, Harbin Medical University, Department of Medicinal Chemistry and Natural Medicine Chemistry, Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268)
3 College of Pharmacy, Harbin Medical University, Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268); Chinese Academy of Medical Sciences, Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Harbin, China (GRID:grid.410736.7); Heilongjiang Academy of Medical Science, Institute of Metabolic Disease, Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268)
4 College of Pharmacy, Harbin Medical University, Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin, China (GRID:grid.410736.7) (ISNI:0000 0001 2204 9268); Chinese Academy of Medical Sciences, Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Harbin, China (GRID:grid.410736.7); Dentistry and Health Sciences University of Melbourne, Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)