Article

Kanglexin delays heart aging by promoting mitophagy

Hui-min Li1, Xin Liu1, Zi-yu Meng1, Lei Wang1, Li-min Zhao1, Hui Chen1, Zhi-xia Wang1, Hao Cui1, Xue-qing Tang1, Xiao-han Li1, Wei-na Han2, Xue Bai1, Yuan Lin1, Heng Liu1, Yong Zhang1,3,4, Bao-feng Yang1,3,5
1 Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
3 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin 150086, China
4 Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China
5 Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne, Melbourne, Australia
Correspondence to: Yong Zhang: hmuzhangyong@hotmail.com, Bao-feng Yang: yangbf@ems.hrbmu.edu.cn,
DOI: 10.1038/s41401-021-00686-5
Received: 18 December 2020
Accepted: 23 April 2021
Advance online: 25 May 2021

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.
Keywords: Kanglexin; emodin; heart aging; Parkin; mitophagy

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