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.
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References
Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.
Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407.
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.
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.
Willis MS, Patterson C. Into the heart: the emerging role of the ubiquitin-proteasome system. J Mol Cell Cardiol. 2006;41:567–79.
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.
Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovascular Res. 1998;39:89–105.
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.
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gao H, Hartnett S, Li Y. Ubiquitin C-terminal hydrolase L1 regulates myoblast proliferation and differentiation. Biochem Biophys Res Commun. 2017;492:96–102.
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.
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.
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.
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.
Larsen CN, Krantz BA, Wilkinson KD. Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry. 1998;37:3358–68.
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.
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.
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.
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.
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.
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.
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).
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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
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DOI: https://doi.org/10.1038/s41440-020-0486-1
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