2. Academic Validation
  3. Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy

Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy

  • Acta Pharmacol Sin. 2022 Aug 10. doi: 10.1038/s41401-022-00956-w.
Lei Wang  # 1,  Xue-Qing Tang  # 1,  Yang Shi  # 1,  Hui-Min Li 1,  Zi-Yu Meng 1,  Hui Chen 1,  Xiao-Han Li 1,  Yong-Chao Chen 1,  Heng Liu 1,  Yang Hong 1,  Heng-Hui Xu 1,  Ling Liu 1,  Limin Zhao 1,  Wei-Na Han 2,  Xin Liu 3 4,  Yong Zhang 5 6 7
Affiliations

Affiliations

  • 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 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. freyaliuxin@163.com.
  • 4 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China. freyaliuxin@163.com.
  • 5 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. hmuzhangyong@hotmail.com.
  • 6 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China. hmuzhangyong@hotmail.com.
  • 7 Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150081, China. hmuzhangyong@hotmail.com.
  • # Contributed equally.
PMID: 35948750 DOI: 10.1038/s41401-022-00956-w
Abstract

Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 μM) and THBru (20, 40 μM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of Mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted Mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during Mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted Mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated Mitophagy and suggests its clinical application prospects.

Keywords

PHB2; antiaging medicine; berberine; heart aging; mitophagy; tetrahydroberberrubine.

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