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BMC Cardiovascular Disorders

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Open Access 01-12-2024 | Heart Failure | Research

Mycn ameliorates cardiac hypertrophy-induced heart failure in mice by mediating the USP2/JUP/Akt/β-catenin cascade

Authors: Weinian Gao, Na Guo, Hongjiang Yan, Shuguang Zhao, Yongquan Sun, Ziying Chen

Published in: BMC Cardiovascular Disorders | Issue 1/2024

Abstract

Background

Pathological cardiac hypertrophy is associated with cardiac dysfunction and is a key risk factor for heart failure and even sudden death. This study investigates the function of Mycn in cardiac hypertrophy and explores the interacting molecules.

Methods

A mouse model of cardiac hypertrophy was induced by isoproterenol (ISO). The cardiac dysfunction was assessed by the heart weight-to-body weight ratio (HW/BW), echocardiography assessment, pathological staining, biomarker detection, and cell apoptosis. Transcriptome alteration in cardiac hypertrophy was analyzed by bioinformatics analysis. Gain- or loss-of-function studies of MYCN proto-oncogene (Mycn), ubiquitin specific peptidase 2 (USP2), and junction plakoglobin (JUP) were performed. The biological functions of Mycn were further examined in ISO-treated cardiomyocytes. The molecular interactions were verified by luciferase assay or immunoprecipitation assays.

Results

Mycn was poorly expressed in ISO-treated mice, and its upregulation reduced HW/BW, cell surface area, oxidative stress, and inflammation while improving cardiac function of mice. It also reduced apoptosis of cardiomyocytes in mice and those in vitro induced by ISO. Mycn bound to the USP2 promoter to activate its transcription. USP2 overexpression exerted similar myocardial protective functions. It stabilized JUP protein by deubiquitination modification, which blocked the Akt/β-catenin pathway. Knockdown of JUP restored phosphorylation of Akt and β-catenin protein level, which negated the protective effects of USP2.

Conclusion

This study demonstrates that Mycn activates USP2 transcription, which mediates ubiquitination and protein stabilization of JUP, thus inactivating the Akt/β-catenin axis and alleviating cardiac hypertrophy-induced heart failure.

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Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245–62.CrossRefPubMed

Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358(13):1370–80.CrossRefPubMed

Gallo S, Vitacolonna A, Bonzano A, Comoglio P, Crepaldi T. ERK: a key player in the pathophysiology of Cardiac Hypertrophy. Int J Mol Sci 2019;20(9).

Samak M, Fatullayev J, Sabashnikov A, Zeriouh M, Schmack B, Farag M, et al. Cardiac hypertrophy: an introduction to Molecular and Cellular basis. Med Sci Monit Basic Res. 2016;22:75–9.CrossRefPubMedPubMedCentral

Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 2015;89(9):1401–38.CrossRefPubMed

Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15(7):387–407.CrossRefPubMed

Ruiz-Perez MV, Henley AB, Arsenian-Henriksson M. The MYCN protein in Health and Disease. Genes (Basel) 2017;8(4).

Harmelink C, Peng Y, DeBenedittis P, Chen H, Shou W, Jiao K. Myocardial mycn is essential for mouse ventricular wall morphogenesis. Dev Biol. 2013;373(1):53–63.CrossRefPubMed

Fu D, Luo J, Wu Y, Zhang L, Li L, Chen H, et al. Angiotensin II-induced calcium overload affects mitochondrial functions in cardiac hypertrophy by targeting the USP2/MFN2 axis. Mol Cell Endocrinol. 2023;571:111938.CrossRefPubMed

10.

Kitamura H, Hashimoto M. USP2-Related Cellular Signaling and Consequent Pathophysiological outcomes. Int J Mol Sci 2021;22(3).

11.

Xiao W, Wang J, Wang X, Cai S, Guo Y, Ye L, et al. Therapeutic targeting of the USP2-E2F4 axis inhibits autophagic machinery essential for zinc homeostasis in cancer progression. Autophagy. 2022;18(11):2615–35.CrossRefPubMedPubMedCentral

12.

Li J, Swope D, Raess N, Cheng L, Muller EJ, Radice GL. Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of beta-catenin signaling. Mol Cell Biol. 2011;31(6):1134–44.CrossRefPubMedPubMedCentral

13.

Lin H, Li Y, Zhu H, Wang Q, Chen Z, Chen L, et al. Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of beta-catenin. Cardiovasc Res. 2020;116(1):101–13.CrossRefPubMed

14.

Laferriere CA, Pang DS. Review of Intraperitoneal Injection of Sodium Pentobarbital as a method of Euthanasia in Laboratory rodents. J Am Assoc Lab Anim Sci. 2020;59(3):254–63.CrossRefPubMedPubMedCentral

15.

Li T, Kuang T, Yang Z, Zhang Q, Zhang W, Fan Y. Co-treatment with Everolimus, an mTOR-Specific antagonist, or downregulation of ELK1 enhances the sensitivity of pancreatic Cancer cells to Genistein. Front Cell Dev Biol. 2021;9:633035.CrossRefPubMedPubMedCentral

16.

Guo Y, Shi DZ, Yin HJ, Chen KJ. Effects of Tribuli saponins on ventricular remodeling after myocardial infarction in hyperlipidemic rats. Am J Chin Med. 2007;35(2):309–16.CrossRefPubMed

17.

Lal H, Ahmad F, Parikh S, Force T. Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease. Circ J. 2014;78(7):1514–9.CrossRefPubMedPubMedCentral

18.

Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res. 2018;42(2):123–32.CrossRefPubMed

19.

Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: Genetics, Pathogenesis, clinical manifestations, diagnosis, and Therapy. Circ Res. 2017;121(7):749–70.CrossRefPubMedPubMedCentral

20.

Ramachandra CJA, Cong S, Chan X, Yap EP, Yu F, Hausenloy DJ. Oxidative stress in cardiac hypertrophy: from molecular mechanisms to novel therapeutic targets. Free Radic Biol Med. 2021;166:297–312.CrossRefPubMed

21.

Shah AK, Bhullar SK, Elimban V, Dhalla NS. Oxidative stress as a mechanism for functional alterations in Cardiac Hypertrophy and Heart failure. Antioxid (Basel) 2021;10(6).

22.

Guan XH, Hong X, Zhao N, Liu XH, Xiao YF, Chen TT, et al. CD38 promotes angiotensin II-induced cardiac hypertrophy. J Cell Mol Med. 2017;21(8):1492–502.CrossRefPubMedPubMedCentral

23.

Senger N, A CP, Marques BVD, Akamine EH, Diniz GP, Campagnole-Santos MJ, et al. Angiotensin-(1–7) prevents T3-induced cardiomyocyte hypertrophy by upregulating FOXO3/SOD1/catalase and downregulating NF-kB. J Cell Physiol. 2021;236(4):3059–72.CrossRefPubMed

24.

Song G, Zhu L, Ruan Z, Wang R, Shen Y. MicroRNA-122 promotes cardiomyocyte hypertrophy via targeting FoxO3. Biochem Biophys Res Commun. 2019;519(4):682–8.CrossRefPubMed

25.

He S, Mansour MR, Zimmerman MW, Ki DH, Layden HM, Akahane K et al. Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. Elife 2016;5.

26.

Genevieve D, de Pontual L, Amiel J, Sarnacki S, Lyonnet S. An overview of isolated and syndromic oesophageal atresia. Clin Genet. 2007;71(5):392–9.CrossRefPubMed

27.

Veas-Perez de Tudela M, Delgado-Esteban M, Cuende J, Bolanos JP, Almeida A. Human neuroblastoma cells with MYCN amplification are selectively resistant to oxidative stress by transcriptionally up-regulating glutamate cysteine ligase. J Neurochem. 2010;113(4):819–25.CrossRefPubMed

28.

Zaytseva O, Kim NH, Quinn LM. MYC in Brain Development and Cancer. Int J Mol Sci 2020;21(20).

29.

Xing J, Li P, Hong J, Wang M, Liu Y, Gao Y, et al. Overexpression of ubiquitin-specific protease 2 (USP2) in the Heart suppressed pressure overload-Induced Cardiac Remodeling. Mediators Inflamm. 2020;2020:4121750.CrossRefPubMedPubMedCentral

30.

Zhang D, Liang C, Li P, Yang L, Hao Z, Kong L, et al. Runt-related transcription factor 1 (Runx1) aggravates pathological cardiac hypertrophy by promoting p53 expression. J Cell Mol Med. 2021;25(16):7867–77.CrossRefPubMedPubMedCentral

31.

Duran J, Lagos D, Pavez M, Troncoso MF, Ramos S, Barrientos G, et al. Ca(2+)/Calmodulin-Dependent protein kinase II and Androgen Signaling pathways modulate MEF2 activity in Testosterone-Induced Cardiac Myocyte Hypertrophy. Front Pharmacol. 2017;8:604.CrossRefPubMedPubMedCentral

32.

Song HK, Hong SE, Kim T, Kim DH. Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. PLoS ONE. 2012;7(4):e35552.CrossRefPubMedPubMedCentral

33.

Baumgarten A, Bang C, Tschirner A, Engelmann A, Adams V, von Haehling S, et al. TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human end-stage dilated cardiomyopathy. Int J Cardiol. 2013;168(2):1447–52.CrossRefPubMed

34.

Wu G, Liu J, Ruan J, Yu S, Wang L, Zhao S, et al. Deleterious rare desmosomal variants contribute to hypertrophic cardiomyopathy and are Associated with distinctive clinical features. Can J Cardiol. 2022;38(1):41–8.CrossRefPubMed

35.

Hsieh PL, Chu PM, Cheng HC, Huang YT, Chou WC, Tsai KL et al. Dapagliflozin mitigates doxorubicin-caused myocardium damage by regulating AKT-Mediated oxidative stress, Cardiac Remodeling, and inflammation. Int J Mol Sci 2022;23(17).

36.

Liu P, Su J, Song X, Wang S. Activation of nuclear beta-catenin/c-Myc axis promotes oxidative stress injury in streptozotocin-induced diabetic cardiomyopathy. Biochem Biophys Res Commun. 2017;493(4):1573–80.CrossRefPubMed

37.

Sen P, Gupta K, Kumari A, Singh G, Pandey S, Singh R. Wnt/beta-Catenin antagonist pyrvinium exerts cardioprotective effects in Polymicrobial Sepsis Model by attenuating Calcium Dyshomeostasis and mitochondrial dysfunction. Cardiovasc Toxicol. 2021;21(7):517–32.CrossRefPubMed

38.

Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009;7(6):e1000121.CrossRefPubMedPubMedCentral

Title: Mycn ameliorates cardiac hypertrophy-induced heart failure in mice by mediating the USP2/JUP/Akt/β-catenin cascade
Authors: Weinian Gao
Na Guo
Hongjiang Yan
Shuguang Zhao
Yongquan Sun
Ziying Chen
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Heart Failure
Published in: BMC Cardiovascular Disorders / Issue 1/2024
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-024-03748-8

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Mycn ameliorates cardiac hypertrophy-induced heart failure in mice by mediating the USP2/JUP/Akt/β-catenin cascade

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Background

Methods

Results

Conclusion

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