Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit

Acta Pharmacologica Sinica volume 44, pages 1777–1789 (2023)Cite this article

Abstract

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. In this study we investigated the role of a histone arginine demethylase, Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy. Cardiac hypertrophy was induced in rats by subcutaneous injection of isoproterenol (ISO, 1.2 mg·kg−1·d−1) for a week. At the end of the experiment, the rats underwent echocardiography, followed by euthanasia and heart collection. We found that JMJD6 levels were compensatorily increased in ISO-induced hypertrophic cardiac tissues, but reduced in patients with heart failure with reduced ejection fraction (HFrEF). Furthermore, we demonstrated that JMJD6 overexpression significantly attenuated ISO-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) evidenced by the decreased cardiomyocyte surface area and hypertrophic genes expression. Cardiac-specific JMJD6 overexpression in rats protected the hearts against ISO-induced cardiac hypertrophy and fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) exacerbated ISO-induced hypertrophic responses in NRCMs. We revealed that JMJD6 interacted with NF-κB p65 in cytoplasm and reduced nuclear levels of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 bound to p65 and demethylated p65 at the R149 residue to inhibit the nuclear translocation of p65, thus inactivating NF-κB signaling and protecting against pathological cardiac hypertrophy. In addition, we found that JMJD6 demethylated histone H3R8, which might be a new histone substrate of JMJD6. These results suggest that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: JMJD6 expression was changed in HFrEF patients and hypertrophic rat hearts.
Fig. 2: JMJD6 negatively regulates ISO-induced cardiac hypertrophy in NRCMs.
Fig. 3: JMJD6 overexpression represses ISO-induced cardiac hypertrophy in rats.
Fig. 4: JMJD6 regulates NF-κB signaling in ISO-induced cardiac hypertrophy in vitro.
Fig. 5: JMJD6 regulates NF-κB signaling in ISO-induced cardiac hypertrophy in vivo.
Fig. 6: JMJD6 decreased the methylation level in ISO-induced cardiac hypertrophy.
Fig. 7: JMJD6 demethylated R149 of p65 to inactivate NF-κB.

Similar content being viewed by others

References

  1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–e596.

    Article  PubMed  Google Scholar 

  2. Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004;109:1580–9.

    Article  PubMed  Google Scholar 

  3. Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol. 2013;14:38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, et al. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J. 2008;29:1224–40.

    Article  CAS  PubMed  Google Scholar 

  5. Mano H. Epigenetic abnormalities in cardiac hypertrophy and heart failure. Environ Health Prev Med. 2008;13:25–29.

    Article  CAS  PubMed  Google Scholar 

  6. Lin Z, Li Z, Guo Z, Cao Y, Li J, Liu P, et al. Epigenetic reader bromodomain containing protein 2 facilitates pathological cardiac hypertrophy via regulating the expression of citrate cycle genes. Front Pharmacol. 2022;13:887991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu CF, Tang WHW. Epigenetics in cardiac hypertrophy and heart failure. JACC Basic Transl Sci. 2019;4:976–93.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li Q, Li ZM, Sun SY, Wang LP, Wang PX, Guo Z, et al. PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy. Acta Pharmacol Sin. 2019;40:589–98.

    Article  CAS  PubMed  Google Scholar 

  9. Li Z, Guo Z, Lan R, Cai S, Lin Z, Li J, et al. The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy. Acta Pharm Sin B. 2021;11:1286–99.

    Article  CAS  PubMed  Google Scholar 

  10. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13:343–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bannister AJ, Kouzarides T. Reversing histone methylation. Nature. 2005;436:1103–6.

    Article  CAS  PubMed  Google Scholar 

  12. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Genome Biol. 2019;20:245.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Peter CJ, Akbarian S. Balancing histone methylation activities in psychiatric disorders. Trends Mol Med. 2011;17:372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cai S, Wang P, Xie T, Li Z, Li J, Lan R, et al. Histone H4R3 symmetric di-methylation by prmt5 protects against cardiac hypertrophy via regulation of Filip1L/beta-catenin. Pharmacol Res. 2020;161:105104.

    Article  CAS  PubMed  Google Scholar 

  16. Pyun JH, Kim HJ, Jeong MH, Ahn BY, Vuong TA, Lee DI, et al. Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nat Commun. 2018;9:5107.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang QJ, Liu ZP. Histone methylations in heart development, congenital and adult heart diseases. Epigenomics. 2015;7:321–30.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang QJ, Chen HZ, Wang L, Liu DP, Hill JA, Liu ZP. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest. 2011;121:2447–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guo Z, Lu J, Li J, Wang P, Li Z, Zhong Y, et al. JMJD3 inhibition protects against isoproterenol-induced cardiac hypertrophy by suppressing beta-MHC expression. Mol Cell Endocrinol. 2018;477:1–14.

    Article  CAS  PubMed  Google Scholar 

  20. Chang B, Chen Y, Zhao Y, Bruick RK. JMJD6 is a histone arginine demethylase. Science. 2007;318:444–7.

    Article  CAS  PubMed  Google Scholar 

  21. Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, et al. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell. 2013;155:1581–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Unoki M, Masuda A, Dohmae N, Arita K, Yoshimatsu M, Iwai Y, et al. Lysyl 5-hydroxylation, a novel histone modification, by Jumonji domain containing 6 (JMJD6). J Biol Chem. 2013;288:6053–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, et al. Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science. 2009;325:90–93.

    Article  CAS  PubMed  Google Scholar 

  24. Poulard C, Rambaud J, Hussein N, Corbo L, Le Romancer M. JMJD6 regulates ERalpha methylation on arginine. PLoS One. 2014;9:e87982.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tikhanovich I, Kuravi S, Artigues A, Villar MT, Dorko K, Nawabi A, et al. Dynamic arginine methylation of tumor necrosis factor (TNF) receptor-associated factor 6 regulates toll-like receptor signaling. J Biol Chem. 2015;290:22236–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tsai WC, Reineke LC, Jain A, Jung SY, Lloyd RE. Histone arginine demethylase JMJD6 is linked to stress granule assembly through demethylation of the stress granule-nucleating protein G3BP1. J Biol Chem. 2017;292:18886–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vrankova S, Barta A, Klimentova J, Dovinova I, Liskova S, Dobesova Z, et al. The regulatory role of nuclear factor kappa B in the heart of hereditary hypertriglyceridemic rat. Oxid Med Cell Longev. 2016;2016:9814038.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Huxford T, Huang DB, Malek S, Ghosh G. The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell. 1998;95:759–70.

    Article  CAS  PubMed  Google Scholar 

  29. Jacobs MD, Harrison SC. Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998;95:749–58.

    Article  CAS  PubMed  Google Scholar 

  30. Huang B, Yang XD, Lamb A, Chen LF. Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell Signal. 2010;22:1282–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu T, Stark GR. NF-kappaB: regulation by methylation. Cancer Res. 2015;75:3692–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ea CK, Baltimore D. Regulation of NF-kappaB activity through lysine monomethylation of p65. Proc Natl Acad Sci USA. 2009;106:18972–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, et al. Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat Immunol. 2011;12:29–36.

    Article  CAS  PubMed  Google Scholar 

  34. Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci USA. 2010;107:46–51.

    Article  CAS  PubMed  Google Scholar 

  35. Yang XD, Huang B, Li M, Lamb A, Kelleher NL, Chen LF. Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. EMBO J. 2009;28:1055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang DB, et al. PRMT5 dimethylates R30 of the p65 subunit to activate NF-kappaB. Proc Natl Acad Sci USA. 2013;110:13516–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hu Y, Guo Z, Lu J, Wang P, Sun S, Zhang Y, et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch Toxicol. 2019;93:533–46.

    Article  CAS  PubMed  Google Scholar 

  38. Liang L, Tu Y, Lu J, Wang P, Guo Z, Wang Q, et al. Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/beta-catenin signaling pathway. J Cell Sci. 2019;132:jcs228478.

    Article  CAS  PubMed  Google Scholar 

  39. Sun S, Hu Y, Zheng Q, Guo Z, Sun D, Chen S, et al. Poly(ADP-ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity. J Cell Biochem. 2019;120:4813–26.

    Article  CAS  PubMed  Google Scholar 

  40. Wang P, Lan R, Guo Z, Cai S, Wang J, Wang Q, et al. Histone demethylase JMJD3 mediated doxorubicin-induced cardiomyopathy by suppressing SESN2 expression. Front Cell Dev Biol. 2020;8:548605.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li J, Huang J, Lu J, Guo Z, Li Z, Gao H, et al. Sirtuin 1 represses PKC-zeta activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy. Br J Pharmacol. 2019;176:416–35.

    CAS  PubMed  Google Scholar 

  42. Lu J, Li J, Hu Y, Guo Z, Sun D, Wang P, et al. Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation. Acta Pharm Sin B 2019;9:782–93.

    Article  PubMed  Google Scholar 

  43. Guo Z, Liao Z, Huang L, Liu D, Yin D, He M. Kaempferol protects cardiomyocytes against anoxia/reoxygenation injury via mitochondrial pathway mediated by SIRT1. Eur J Pharmacol. 2015;761:245–53.

    Article  CAS  PubMed  Google Scholar 

  44. Li Z, Zhang X, Guo Z, Zhong Y, Wang P, Li J, et al. SIRT6 suppresses NFATc4 expression and activation in cardiomyocyte hypertrophy. Front Pharmacol. 2018;9:1519.

    Article  CAS  PubMed  Google Scholar 

  45. Guo Z, Valenzuela Ripoll C, Picataggi A, Rawnsley D, Ozcan M, Chirinos J, et al. Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury. JACC Basic Transl Sci. 2023;8:340–55.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ozcan M, Guo Z, Valenzuela Ripoll C, Diab A, Picataggi A, Rawnsley D, et al. Sustained alternate day fasting potentiates doxorubicin cardiotoxicity. Cell Metab. 2023. Online ahead of print. https://doi.org/10.1016/j.cmet.2023.02.006.

  47. Guo Z, Zhang Y, Liu C, Youn JY, Cai H. Toll-like receptor 2 (TLR2) knockout abrogates diabetic and obese phenotypes while restoring endothelial function via inhibition of NOX1. Diabetes. 2021;70:2107–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Luo W, Wang Y, Yang H, Dai C, Hong H, Li J, et al. Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling. Aging (Albany NY). 2018;10:1722–44.

    Article  CAS  PubMed  Google Scholar 

  49. Chen H, Xue Y, Huang N, Yao X, Sun Z. MeMo: a web tool for prediction of protein methylation modifications. Nucleic Acids Res. 2006;34:W249–W253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Javan H, Szucsik AM, Li L, Schaaf CL, Salama ME, Selzman CH. Cardiomyocyte p65 nuclear factor-kappaB is necessary for compensatory adaptation to pressure overload. Circ Heart Fail. 2015;8:109–18.

    Article  CAS  PubMed  Google Scholar 

  51. Gupta S, Young D, Maitra RK, Gupta A, Popovic ZB, Yong SL, et al. Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol. 2008;375:637–49.

    Article  CAS  PubMed  Google Scholar 

  52. Hong HQ, Lu J, Fang XL, Zhang YH, Cai Y, Yuan J, et al. G3BP2 is involved in isoproterenol-induced cardiac hypertrophy through activating the NF-kappaB signaling pathway. Acta Pharmacol Sin. 2018;39:184–94.

    Article  CAS  PubMed  Google Scholar 

  53. Yu SS, Cai Y, Ye JT, Pi RB, Chen SR, Liu PQ, et al. Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-kappaB-dependent transcriptional activity. Br J Pharmacol. 2013;168:117–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem. 1999;274:30353–6.

    Article  CAS  PubMed  Google Scholar 

  55. Sasaki CY, Barberi TJ, Ghosh P, Longo DL. Phosphorylation of RelA/p65 on serine 536 defines an I{kappa}B{alpha}-independent NF-{kappa}B pathway. J Biol Chem. 2005;280:34538–47.

    Article  CAS  PubMed  Google Scholar 

  56. Backs J, Olson EN. Control of cardiac growth by histone acetylation/deacetylation. Circ Res. 2006;98:15–24.

    Article  CAS  PubMed  Google Scholar 

  57. Ooi JY, Tuano NK, Rafehi H, Gao XM, Ziemann M, Du XJ, et al. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10:418–30.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, et al. Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci USA. 2013;110:20164–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zang R, Tan Q, Zeng F, Wang D, Yu S, Wang Q. JMJD1A represses the development of cardiomyocyte hypertrophy by regulating the expression of catalase. Biomed Res Int. 2020;2020:5081323.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Yu S, Li Y, Zhao H, Wang Q, Chen P. The Histone demethylase JMJD1C regulates CAMKK2-AMPK signaling to participate in cardiac hypertrophy. Front Physiol. 2020;11:539.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rosales W, Lizcano F. The histone demethylase JMJD2A modulates the induction of hypertrophy markers in iPSC-derived cardiomyocytes. Front Genet. 2018;9:14.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bristow MR, Kao DP, Breathett KK, Altman NL, Gorcsan J 3rd, Gill EA, et al. Structural and functional phenotyping of the failing heart: Is the left ventricular ejection fraction obsolete? JACC Heart Fail. 2017;5:772–81.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810–52.

    Article  PubMed  Google Scholar 

  64. Purcell NH, Tang G, Yu C, Mercurio F, DiDonato JA, Lin A. Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proc Natl Acad Sci USA. 2001;98:6668–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zelarayan L, Renger A, Noack C, Zafiriou MP, Gehrke C, van der Nagel R, et al. NF-kappaB activation is required for adaptive cardiac hypertrophy. Cardiovasc Res. 2009;84:416–24.

    Article  CAS  PubMed  Google Scholar 

  66. Zou J, Li H, Chen X, Zeng S, Ye J, Zhou C, et al. C/EBPbeta knockdown protects cardiomyocytes from hypertrophy via inhibition of p65-NFkappaB. Mol Cell Endocrinol. 2014;390:18–25.

    Article  CAS  PubMed  Google Scholar 

  67. Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem. 2002;277:3863–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

ZG was supported by the American Heart Association Postdoctoral Fellowship (898679). JL was supported by National Natural Science Foundation of China (82173808), Natural Science Foundation of Guangdong Province (2021B1515020100) and Guangzhou Basic and Applied Basic Research Project (202102020173). WWL was supported by National Natural Science Foundation of China (82003746). PQL was supported by National Natural Science Foundation of China (U21A20419, 81872860), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), and National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004). JGZ was supported by Academic Promotion Program of Shandong First Medical University (2019LJ003). LW was supported by the Project of Shandong Medical and Health Science and Technology (202002040923).

Author information

Author notes

  1. These authors contributed equally: Zhen Guo, Yue-huai Hu and Guo-shuai Feng

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271016, China

    Zhen Guo, Ji-guo Zhang, Lei Wang & Pei-qing Liu

  2. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation; Guangdong Engineering Laboratory of Druggability and New Drug Evaluation; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, 510006, China

    Zhen Guo, Yue-huai Hu, Guo-shuai Feng, Zhen-zhen Li, Si-dong Cai, Qian-qian Wang, Wen-wei Luo, Qian Li, Li-ying Liang, Jing Lu & Pei-qing Liu

  3. Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Zhen Guo, Guo-shuai Feng, Carla Valenzuela Ripoll & Ali Javaheri

  4. Department of Cardiac Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Zhong-kai Wu

Authors
  1. Zhen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue-huai Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guo-shuai Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carla Valenzuela Ripoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen-zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Si-dong Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qian-qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen-wei Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Li-ying Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhong-kai Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ji-guo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ali Javaheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Pei-qing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZG and YHH performed the study, analyzed the data, wrote and revised the manuscript. GSF, ZZL, SDC, QQW and WWL contributed to the animal experiments. GSF, QL, LYL, LW and JGZ contributed to the acquisition of data and data interpretation. CVR contributed to the language polish. AJ provided the TAC mice cardiac tissues. ZKW provided heart tissues from humans with heart failure. ZG, JL and PQL made the hypothesis and participated in the experimental design, and manuscript preparation. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Lei Wang, Jing Lu or Pei-qing Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, Z., Hu, Yh., Feng, Gs. et al. JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit. Acta Pharmacol Sin 44, 1777–1789 (2023). https://doi.org/10.1038/s41401-023-01086-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01086-7

Keywords

Search

Advanced search

Quick links