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

Acta Pharmacologica Sinica volume 44, pages 332–344 (2023)Cite this article

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.

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Fig. 1: THBru reduces cardiac diastolic dysfunction in D-gal-induced aging mice.
Fig. 2: THBru attenuates cardiac remodeling and delays heart aging in aging mice.
Fig. 3: THBru inhibits cardiomyocyte senescence.
Fig. 4: THBru promotes mitophagy in vitro and in vivo.
Fig. 5: THBru increases the expression of PHB2 by stabilizing PHB2 mRNA in aging hearts.
Fig. 6: Knockdown of PHB2 attenuates mitophagy activated by THBru.
Fig. 7: PHB2 plays a pivotal role in the antiaging effect of THBru.
Fig. 8

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

References

  1. Khan SS, Singer BD, Vaughan DE. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell. 2017;16:624–33.

    Article  CAS  Google Scholar 

  2. Ferrucci L, Gonzalez-Freire M, Fabbri E, Simonsick E, Tanaka T, Moore Z, et al. Measuring biological aging in humans: a quest. Aging Cell. 2020;19:e13080.

    Article  CAS  Google Scholar 

  3. Mensah GA, Roth GA, Fuster V. The global burden of cardiovascular diseases and risk factors: 2020 and beyond. J Am Coll Cardiol. 2019;74:2529–32.

    Article  Google Scholar 

  4. Obas V, Vasan RS. The aging heart. Clin Sci. 2018;132:1367–82.

    Article  CAS  Google Scholar 

  5. Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757–72.

    Article  CAS  Google Scholar 

  6. Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol. 2017;69:1952–67.

    Article  Google Scholar 

  7. Horn MA, Trafford AW. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J Mol Cell Cardiol. 2016;93:175–85.

    Article  CAS  Google Scholar 

  8. Dunbar SB, Khavjou OA, Bakas T, Hunt G, Kirch RA, Leib AR, et al. Projected costs of informal caregiving for cardiovascular disease: 2015 to 2035: a policy statement from the American Heart Association. Circulation. 2018;137:e558–77.

    Article  Google Scholar 

  9. Guzman-Castillo M, Ahmadi-Abhari S, Bandosz P, Capewell S, Steptoe A, Singh-Manoux A, et al. Forecasted trends in disability and life expectancy in England and Wales up to 2025: a modelling study. Lancet Public Health. 2017;2:e307–13.

    Article  Google Scholar 

  10. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev. 2019;99:1047–78.

    Article  CAS  Google Scholar 

  11. Kubben N, Misteli T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol. 2017;18:595–609.

    Article  CAS  Google Scholar 

  12. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. 2016;166:822–39.

    Article  CAS  Google Scholar 

  13. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.

    Article  CAS  Google Scholar 

  14. Sica V, Galluzzi L, Bravo-San Pedro JM, Izzo V, Maiuri MC, Kroemer G. Organelle-specific initiation of autophagy. Mol Cell. 2015;59:522–39.

    Article  CAS  Google Scholar 

  15. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. 2018;19:579–93.

    Article  CAS  Google Scholar 

  16. Nakamura S, Oba M, Suzuki M, Takahashi A, Yamamuro T, Fujiwara M, et al. Suppression of autophagic activity by Rubicon is a signature of aging. Nat Commun. 2019;10:847.

    Article  Google Scholar 

  17. Ren J, Zhang Y. Targeting autophagy in aging and aging-related cardiovascular diseases. Trends Pharmacol Sci. 2018;39:1064–76.

    Article  CAS  Google Scholar 

  18. Ajoolabady A, Aslkhodapasandhokmabad H, Aghanejad A, Zhang Y, Ren J. Mitophagy receptors and mediators: therapeutic targets in the management of cardiovascular ageing. Ageing Res Rev. 2020;62:101129.

    Article  CAS  Google Scholar 

  19. Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K. Molecular mechanisms and physiological functions of mitophagy. EMBO J. 2021;40:e104705.

    Article  CAS  Google Scholar 

  20. Lahiri V, Klionsky DJ. PHB2/prohibitin 2: an inner membrane mitophagy receptor. Cell Res. 2017;27:311–2.

    Article  CAS  Google Scholar 

  21. Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell. 2017;168:224–38.e10.

    Article  CAS  Google Scholar 

  22. Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab. 2009;20:394–401.

    Article  CAS  Google Scholar 

  23. Xiao Y, Zhou Y, Lu Y, Zhou K, Cai W. PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver. Cell Death Dis. 2018;9:160.

    Article  Google Scholar 

  24. Yan C, Gong L, Chen L, Xu M, Abou-Hamdan H, Tang M, et al. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy. 2020;16:419–34.

    Article  CAS  Google Scholar 

  25. Huo S, Shi W, Ma H, Yan D, Luo P, Guo J, et al. Alleviation of inflammation and oxidative stress in pressure overload-induced cardiac remodeling and heart failure via IL-6/STAT3 inhibition by raloxifene. Oxid Med Cell Longev. 2021;2021:6699054.

    Article  Google Scholar 

  26. Wang J, Zhu P, Li R, Ren J, Zhang Y, Zhou H. Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2. Theranostics. 2020;10:384–97.

    Article  CAS  Google Scholar 

  27. Zhang H, Yin C, Liu X, Bai X, Wang L, Xu H, et al. Prohibitin 2/PHB2 in parkin-mediated mitophagy: a potential therapeutic target for non-small cell lung carcinoma. Med Sci Monit. 2020;26:e923227.

    Article  CAS  Google Scholar 

  28. Zhang Y, Li X, Zhang Q, Li J, Ju J, Du N, et al. Berberine hydrochloride prevents postsurgery intestinal adhesion and inflammation in rats. J Pharmacol Exp Ther. 2014;349:417–26.

    Article  Google Scholar 

  29. Liu X, Wei Y, Bai X, Li M, Li H, Wang L, et al. Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1. Acta Pharm Sin B. 2020;10:812–24.

    Article  CAS  Google Scholar 

  30. Ortiz LM, Lombardi P, Tillhon M, Scovassi AI. Berberine, an epiphany against cancer. Molecules. 2014;19:12349–67.

    Article  Google Scholar 

  31. Ahmed T, Gilani AU, Abdollahi M, Daglia M, Nabavi SF, Nabavi SM. Berberine and neurodegeneration: A review of literature. Pharmacol Rep. 2015;67:970–9.

    Article  CAS  Google Scholar 

  32. Dang Y, An Y, He J, Huang B, Zhu J, Gao M, et al. Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression. Aging Cell. 2020;19:e13060.

    Article  CAS  Google Scholar 

  33. Jin Y, Khadka DB, Cho WJ. Pharmacological effects of berberine and its derivatives: a patent update. Expert Opin Ther Pat. 2016;26:229–43.

    Article  CAS  Google Scholar 

  34. Li YH, Li Y, Yang P, Kong WJ, You XF, Ren G, et al. Design, synthesis, and cholesterol-lowering efficacy for prodrugs of berberrubine. Bioorg Med Chem. 2010;18:6422–8.

    Article  CAS  Google Scholar 

  35. Cheng Z, Chen AF, Wu F, Sheng L, Zhang HK, Gu M, et al. 8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models. Bioorg Med Chem. 2010;18:5915–24.

    Article  CAS  Google Scholar 

  36. Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57:1414–8.

    Article  CAS  Google Scholar 

  37. Ge HX, Zhang J, Kai C, Liu JH, Yu BY. Regio- and enantio-selective glycosylation of tetrahydroprotoberberines by Gliocladium deliquescens NRRL1086 resulting in unique alkaloidal glycosides. Appl Microbiol Biotechnol. 2012;93:2357–64.

    Article  CAS  Google Scholar 

  38. Zhao W, Ge H, Liu K, Chen X, Zhang J, Liu B. Nandinine, a derivative of berberine, inhibits inflammation and reduces insulin resistance in adipocytes via regulation of AMP-kinase activity. Planta Med. 2017;83:203–9.

    CAS  Google Scholar 

  39. Yu X, Yu S, Chen L, Liu H, Zhang J, Ge H, et al. Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-κB signaling pathways. Biomed Pharmacother. 2016;82:489–97.

    Article  CAS  Google Scholar 

  40. Mi G, Liu S, Zhang J, Liang H, Gao Y, Li N, et al. Levo-tetrahydroberberrubine produces anxiolytic-like effects in mice through the 5-HT1A receptor. PLoS One. 2017;12:e0168964.

    Article  Google Scholar 

  41. Wang C, Cai Z, Wang W, Wei M, Si X, Shang Y, et al. Piperine regulates glycogen synthase kinase-3β-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model. J Nutr Biochem. 2020;75:108261.

    Article  CAS  Google Scholar 

  42. Bai X, Yang C, Jiao L, Diao H, Meng Z, Wang L, et al. LncRNA MIAT impairs cardiac contractile function by acting on mitochondrial translocator protein TSPO in a mouse model of myocardial infarction. Signal Transduct Target Ther. 2021;6:172.

    Article  CAS  Google Scholar 

  43. Schnelle M, Catibog N, Zhang M, Nabeebaccus AA, Anderson G, Richards DA, et al. Echocardiographic evaluation of diastolic function in mouse models of heart disease. J Mol Cell Cardiol. 2018;114:20–8.

    Article  CAS  Google Scholar 

  44. Zhang Y, Jiao L, Sun L, Li Y, Gao Y, Xu C, et al. LncRNA ZFAS1 as a SERCA2a inhibitor to cause intracellular Ca2+ overload and contractile dysfunction in a mouse model of myocardial infarction. Circ Res. 2018;122:1354–68.

    Article  CAS  Google Scholar 

  45. Li HM, Liu X, Meng ZY, Wang L, Zhao LM, Chen H, et al. Kanglexin delays heart aging by promoting mitophagy. Acta Pharmacol Sin. 2022;43:613–23.

    Article  CAS  Google Scholar 

  46. Zhang Y, Sun L, Xuan L, Pan Z, Hu X, Liu H, et al. Long non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling. Nat Commun. 2018;9:4176.

    Article  Google Scholar 

  47. Wang Q, Qian Y, Wang Q, Yang YF, Ji S, Song W, et al. Metabolites identification of bioactive licorice compounds in rats. J Pharm Biomed Anal. 2015;115:515–22.

    Article  CAS  Google Scholar 

  48. Rodriguez-Enriquez S, Kai Y, Maldonado E, Currin RT, Lemasters JJ. Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes. Autophagy. 2009;5:1099–106.

    Article  CAS  Google Scholar 

  49. Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-based chronic disease, adiposity and dysglycemia drivers: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:525–38.

    Article  CAS  Google Scholar 

  50. Kim HL, Lim WH, Seo JB, Chung WY, Kim SH, Kim MA, et al. Association between arterial stiffness and left ventricular diastolic function in relation to gender and age. Medicine. 2017;96:e5783.

    Article  Google Scholar 

  51. Shirakabe A, Ikeda Y, Sciarretta S, Zablocki DK, Sadoshima J. Aging and autophagy in the heart. Circ Res. 2016;118:1563–76.

    Article  CAS  Google Scholar 

  52. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2:113–22.

    Article  Google Scholar 

  53. Johnson SC, Sangesland M, Kaeberlein M, Rabinovitch PS. Modulating mTOR in aging and health. Interdiscip Top Gerontol. 2015;40:107–27.

    Article  Google Scholar 

  54. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.

    Article  CAS  Google Scholar 

  55. Blagosklonny MV. Rapamycin for longevity: opinion article. Aging. 2019;11:8048–67.

    Article  CAS  Google Scholar 

  56. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22:1428–38.

    Article  CAS  Google Scholar 

  57. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17:679–90.

    Article  CAS  Google Scholar 

  58. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24:795–806.

    Article  CAS  Google Scholar 

  59. Yoshino J, Baur JA, Imai SI. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;27:513–28.

    Article  CAS  Google Scholar 

  60. Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, et al. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010;142:39–51.

    Article  CAS  Google Scholar 

  61. Torregrosa-Muñumer R, Vara E, Fernández-Tresguerres J, Gredilla R. Resveratrol supplementation at old age reverts changes associated with aging in inflammatory, oxidative and apoptotic markers in rat heart. Eur J Nutr. 2021;60:2683–93.

    Article  Google Scholar 

  62. Onishi M, Okamoto K. Mitochondrial clearance: mechanisms and roles in cellular fitness. FEBS Lett. 2021;595:1239–63.

    Article  CAS  Google Scholar 

  63. Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120:1812–24.

    Article  CAS  Google Scholar 

  64. Ikeda Y, Shirakabe A, Brady C, Zablocki D, Ohishi M, Sadoshima J. Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. J Mol Cell Cardiol. 2015;78:116–22.

    Article  CAS  Google Scholar 

  65. Li Y, Ma Y, Song L, Yu L, Zhang L, Zhang Y, et al. SIRT3 deficiency exacerbates p53/Parkin‑mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts. Int J Mol Med. 2018;41:3517–26.

    CAS  Google Scholar 

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Acknowledgements

We thank Qi Wang, Zhi-xia Wang, Hao Cui and Bo Peng for their advice to the study. This work was supported by the National Natural Science Foundation of China (81773735, 81903610, 91949130, 81961138018), National Key R&D Program of China (2017YFC1702003) and HMU Marshal Initiative Funding (HMUMIF-21022).

Funding

This study was funded by the National Natural Science Foundation of China (91949130, 81961138018, 81903610) and HMU Marshal Initiative Funding (HMUMIF-21022).

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Author notes

  1. These authors contributed equally: Lei Wang, Xue-qing Tang, Yang Shi

Authors and 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

    Lei Wang, Xue-qing Tang, Yang Shi, Hui-min Li, Zi-yu Meng, Hui Chen, Xiao-han Li, Yong-chao Chen, Heng Liu, Yang Hong, Heng-hui Xu, Ling Liu, Limin Zhao, Xin Liu & Yong Zhang

  2. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China

    Wei-na Han

  3. Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China

    Xin Liu & Yong Zhang

  4. Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150081, China

    Yong Zhang

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  1. Lei Wang
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Contributions

YZ and XL conceived and designed the study. LW, XQT, YS performed major experiments, drafted the manuscript and analyzed the data. HML, ZYM, and HC performed Western blot, immunochemistry, and qPCR experiments. XHL, YCC, HL, and YH performed primary cell culture and transfection experiments. LMZ, HHX, and LL performed animal experiments. WNH synthesized THBru and analyzed the data. All authors edited the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Xin Liu or Yong Zhang.

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The authors declare no competing interests.

Ethics approval

All procedures were approved by the Institutional Animal Care and Use Committee of Harbin Medical University [Protocol (2009)-11]. The use of animals was compliant with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). All sacrifices were performed under anesthesia, and every effort was made to minimize animal suffering.

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Wang, L., Tang, Xq., Shi, Y. et al. Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy. Acta Pharmacol Sin 44, 332–344 (2023). https://doi.org/10.1038/s41401-022-00956-w

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Keywords

  • heart aging
  • berberine
  • tetrahydroberberrubine
  • mitophagy
  • PHB2
  • antiaging medicine

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