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:

Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats

Abstract

Cardiac remodeling is an important pathological process ultimately leading to heart failure. Ubiquitin carboxy-terminal hydrolase 1 (UCHL1) is a deubiquitinase that plays a critical role in neurodegenerative diseases and cancer. However, its role in cardiac remodeling in spontaneously hypertensive rats remains unclear. Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were administered the UCHL1 inhibitor LDN-57444 (20 μg/kg/day) from 2 months of age for 4 months. Blood pressure, cardiac hypertrophy, fibrosis, inflammation, and oxidative stress were evaluated by the tail-cuff system, echocardiography, and histological analysis. Gene and protein expression levels were examined by real-time PCR and immunoblotting analysis. At 6 months of age, the expression of UCHL at the mRNA and protein levels was significantly upregulated in SHRs compared with WKYs. Moreover, systolic blood pressure, cardiac performance, left ventricular (LV) hypertrophy, fibrosis, inflammation, and superoxide production were significantly increased in SHRs compared with WKYs, and these effects were markedly attenuated by LDN-57444 after 4 months of administration. These beneficial actions were possibly associated with a reduction in blood pressure and inactivation of multiple signaling pathways, including AKT, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3, and NF-κB. In conclusion, the results indicate that UCHL1 is involved in hypertensive cardiac remodeling in SHRs, and targeting UCHL1 activity may be a novel potential therapeutic approach for the treatment of hypertensive heart diseases.

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

Access options

Buy this article

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.

    Article  CAS  PubMed  Google Scholar 

  2. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407.

    Article  CAS  PubMed  Google Scholar 

  3. Li N, Wang HX, Han QY, Li WJ, Zhang YL, Du J, et al. Activation of the cardiac proteasome promotes angiotension II-induced hypertrophy by down-regulation of ATRAP. J Mol Cell Cardiol. 2015;79:303–14.

    Article  CAS  PubMed  Google Scholar 

  4. Li J, Wang S, Bai J, Yang XL, Zhang YL, Che YL, et al. Novel role for the immunoproteasome subunit PSMB10 in angiotensin II-induced atrial fibrillation in mice. Hypertension. 2018;71:866–76.

    Article  CAS  PubMed  Google Scholar 

  5. Willis MS, Patterson C. Into the heart: the emerging role of the ubiquitin-proteasome system. J Mol Cell Cardiol. 2006;41:567–79.

    Article  CAS  PubMed  Google Scholar 

  6. Bishop P, Rocca D, Henley JM. Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction. Biochemical J. 2016;473:2453–62.

    Article  CAS  Google Scholar 

  7. Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovascular Res. 1998;39:89–105.

    Article  CAS  Google Scholar 

  8. Bi HL, Zhang YL, Yang J, Shu Q, Yang XL, Yan X, et al. Inhibition of UCHL1 by LDN-57444 attenuates Ang II-induced atrial fibrillation in mice. Hypertens Res. 2020;43:168–77.

    Article  CAS  PubMed  Google Scholar 

  9. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang YL, Geng C, Yang J, Fang J, Yan X, Li PB, et al. Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats. Biochim Biophys Acta Mol Basis Dis. 2019;1865:165551.

    Article  CAS  PubMed  Google Scholar 

  11. Sundaram A, Siew Keah L, Sirajudeen KN, Singh HJ. Upregulation of catalase and downregulation of glutathione peroxidase activity in the kidney precede the development of hypertension in pre-hypertensive SHR. Hypertension Res: Off J Jpn Soc Hypertens. 2013;36:213–8.

    Article  CAS  Google Scholar 

  12. Dolinsky VW, Chan AY, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JR. Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation. 2009;119:1643–52.

    Article  CAS  PubMed  Google Scholar 

  13. Shu Q, Lai S, Wang XM, Zhang YL, Yang XL, Bi HL, et al. Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. Biochemical biophysical Res Commun. 2018;505:317–24.

    Article  CAS  Google Scholar 

  14. Yan W, Bi HL, Liu LX, Li NN, Liu Y, Du J, et al. Knockout of immunoproteasome subunit beta2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice. Biochem Biophys Res Commun. 2017;490:84–90.

    Article  CAS  PubMed  Google Scholar 

  15. Xie X, Bi HL, Lai S, Zhang YL, Li N, Cao HJ, et al. The immunoproteasome catalytic beta5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation. Sci Adv. 2019;5:eaau0495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim HJ, Kim YM, Lim S, Nam YK, Jeong J, Kim HJ, et al. Ubiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasis. Oncogene. 2009;28:117–27.

    Article  CAS  PubMed  Google Scholar 

  17. Hartnett S, Zhang F, Abitz A, Li Y. Ubiquitin C-terminal hydrolase L1 interacts with choline transporter in cholinergic cells. Neurosci Lett. 2014;564:115–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, Pohl J. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science. 1989;246:670–3.

    Article  CAS  PubMed  Google Scholar 

  19. Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, et al. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem. 2004;279:13256–64.

    Article  CAS  PubMed  Google Scholar 

  20. Gao H, Freeling J, Wu P, Liang AP, Wang X, Li Y. UCHL1 regulates muscle fibers and mTORC1 activity in skeletal muscle. Life Sci. 2019;233:116699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao H, Hartnett S, Li Y. Ubiquitin C-terminal hydrolase L1 regulates myoblast proliferation and differentiation. Biochem Biophys Res Commun. 2017;492:96–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Drobysheva A, Ahmad M, White R, Wang HW, Leenen FH. Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade. Am J Physiol Heart Circ Physiol. 2013;305:H1817–29.

    Article  CAS  PubMed  Google Scholar 

  23. Rajagopalan V, Zhao M, Reddy S, Fajardo G, Wang X, Dewey S, et al. Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure. Am J Physiol Heart Circ Physiol. 2013;305:H551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang X, Guo L, Niu T, Shao L, Li H, Wu W, et al. Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation. PLoS One. 2014;9:e94658.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, et al. Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum Mol Genet. 2003;12:1945–58.

    Article  CAS  PubMed  Google Scholar 

  26. Larsen CN, Krantz BA, Wilkinson KD. Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry. 1998;37:3358–68.

    Article  CAS  PubMed  Google Scholar 

  27. Goto Y, Zeng L, Yeom CJ, Zhu Y, Morinibu A, Shinomiya K, et al. UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1alpha. Nat Commun. 2015;6:6153.

    Article  CAS  PubMed  Google Scholar 

  28. Nakashima R, Goto Y, Koyasu S, Kobayashi M, Morinibu A, Yoshimura M, et al. UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization. Sci Rep. 2017;7:6879.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wilson CL, Murphy LB, Leslie J, Kendrick S, French J, Fox CR, et al. Ubiquitin C-terminal hydrolase 1: a novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease. J Hepatol. 2015;63:1421–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang M, Cai F, Zhang S, Zhang S, Song W. Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer’s progression in vivo. Sci Rep. 2014;4:7298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wenzel P, Knorr M, Kossmann S, Stratmann J, Hausding M, Schuhmacher S, et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation. 2011;124:1370–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the State Key Program of the National Natural Science Foundation of China 81630009 (H-HL), the Dalian High-Level Talents Innovation and Entrepreneurship Projects 2015R019 (H-HL), and the Chang Jiang Scholar Program of China T2011160 (H-HL).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Tao Cong or Hui-Hua Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, X., Zhang, YL., Fu, Tt. et al. Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats. Hypertens Res 43, 1089–1098 (2020). https://doi.org/10.1038/s41440-020-0486-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-0486-1

Search

Quick links