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Open Access 01-12-2018 | Research article

Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice

Authors: Robert H. Oakley, Matthew J. Campen, Michael L. Paffett, Xin Chen, Zhongjing Wang, Traci L. Parry, Carolyn Hillhouse, John A. Cidlowski, Monte S. Willis

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

Background

We recently identified a role for the muscle-specific ubiquitin ligase MuRF1 in right-sided heart failure secondary to pulmonary hypertension induced by chronic hypoxia (CH). MuRF1−/− mice exposed to CH are resistant to right ventricular (RV) dysfunction whereas MuRF1 Tg + mice exhibit impaired function indicative of heart failure. The present study was undertaken to understand the underlying transcriptional alterations in the RV of MuRF1−/− and MuRF1 Tg + mice.

Methods

Microarray analysis was performed on RNA isolated from the RV of MuRF1−/−, MuRF1 Tg+, and wild-type control mice exposed to CH.

Results

MuRF1−/− RV differentially expressed 590 genes in response to CH. Analysis of the top 66 genes (> 2-fold or < − 2-fold) revealed significant associations with oxidoreductase, transcription regulation, and transmembrane component annotations. The significant genes had promoters enriched for HOXD12, HOXC13, and RREB-1 protein transcription factor binding sites. MuRF1 Tg + RV differentially expressed 150 genes in response to CH. Analysis of the top 45 genes (> 3-fold or < − 3-fold) revealed significant associations with oxidoreductase-metabolic, glycoprotein-transmembrane-integral proteins, and alternative splicing/splice variant annotations. The significant genes were enriched for promoters with ZIC1 protein transcription factor binding sites.

Conclusions

The differentially expressed genes in MuRF1−/− and MuRF1 Tg + RV after CH have common functional annotations related to oxidoreductase (including antioxidant) and transmembrane component functions. Moreover, the functionally-enhanced MuRF1−/− hearts regulate genes related to transcription, homeobox proteins, and kinases/phosphorylation. These studies also reveal potential indirect effects of MuRF1 through regulating Rreb-1, and they reveal mechanisms by which MuRF1 may transcriptionally regulate anti-oxidant systems in the face of right heart failure.

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Zornoff LA, Skali H, Pfeffer MA, St John Sutton M, Rouleau JL, Lamas GA, Plappert T, Rouleau JR, Moye LA, Lewis SJ, et al. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol. 2002;39(9):1450–5.CrossRef

Drake JI, Gomez-Arroyo J, Dumur CI, Kraskauskas D, Natarajan R, Bogaard HJ, Fawcett P, Voelkel NF. Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension. Physiol Genomics. 2013;45(12):449–61.CrossRef

Guihaire J, Noly PE, Schrepfer S, Mercier O. Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: insights from experimental studies. Arch Cardiovasc Dis. 2015;108(10):519–29.

Ikeda S, Satoh K, Kikuchi N, Miyata S, Suzuki K, Omura J, Shimizu T, Kobayashi K, Kobayashi K, Fukumoto Y, et al. Crucial role of rho-kinase in pressure overload-induced right ventricular hypertrophy and dysfunction in mice. Arterioscler Thromb Vasc Biol. 2014;34(6):1260–71.CrossRef

Ryan JJ, Archer SL. The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res. 2014;115(1):176–88.CrossRef

Piao L, Sidhu VK, Fang YH, Ryan JJ, Parikh KS, Hong Z, Toth PT, Morrow E, Kutty S, Lopaschuk GD, et al. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl). 2013;91(3):333–46.CrossRef

Piao L, Fang YH, Parikh K, Ryan JJ, Toth PT, Archer SL. Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension. J Mol Med (Berl). 2013;91(10):1185–97.CrossRef

Willis MS, Ike C, Li L, Wang DZ, Glass DJ, Patterson C. Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo. Circ Res. 2007;100(4):456–9.CrossRef

Wadosky KM, Rodriguez JE, Hite RL, Min JN, Walton BL, Willis MS. Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling. Am J Physiol Endocrinol Metab. 2014;306(7):E723–39.CrossRef

10.

Wadosky KM, Berthiaume JM, Tang W, Zungu M, Portman MA, Gerdes AM, Willis MS. MuRF1 mono-ubiquitinates TRalpha to inhibit T3-induced cardiac hypertrophy in vivo. J Mol Endocrinol. 2016;56(3):273–90.CrossRef

11.

Campen MJ, Paffett ML, Colombo ES, Lucas SN, Anderson T, Nysus M, Norenberg JP, Gershman B, Hesterman J, Hoppin J, et al. Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling. PLoS One. 2014;9(5):e97084.CrossRef

12.

Willis MS, Schisler JC, Li L, Rodriguez JE, Hilliard EG, Charles PC, Patterson C. Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo. Circ Res. 2009;105(1):80–8.CrossRef

13.

Campen MJ, Shimoda LA, O'Donnell CP. Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol (1985). 2005;99(5):2028–35.CrossRef

14.

Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45(D1):D362–8.CrossRef

15.

Franceschini A, Lin J, von Mering C, Jensen LJ. SVD-phy: improved prediction of protein functional associations through singular value decomposition of phylogenetic profiles. Bioinformatics. 2016;32(7):1085–7.CrossRef

16.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52.CrossRef

17.

Huang d W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.CrossRef

18.

Huang d W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1):1–13.CrossRef

19.

Willis MS, Rojas M, Li L, Selzman CH, Tang RH, Stansfield WE, Rodriguez JE, Glass DJ, Patterson C. Muscle ring finger 1 mediates cardiac atrophy in vivo. Am J Physiol Heart Circ Physiol. 2009;296(4):H997–H1006.CrossRef

20.

Oakley RH, Ren R, Cruz-Topete D, Bird GS, Myers PH, Boyle MC, Schneider MD, Willis MS, Cidlowski JA. Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. Proc Natl Acad Sci U S A. 2013;110(42):17035–40.CrossRef

21.

Jenssen TK, Laegreid A, Komorowski J, Hovig E. A literature network of human genes for high-throughput analysis of gene expression. Nat Genet. 2001;28(1):21–8.

22.

Tissue-specific Gene Expression and Regulation (TiGER). http://bioinfo.wilmer.jhu.edu/tiger/db_tf/RREB-1-index.html. Accessed 19 Feb 2018.

23.

Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol. 2003;65:45–79.CrossRef

24.

Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007;356(11):1140–51.CrossRef

25.

Rodriguez JE, Liao JY, He J, Schisler JC, Newgard CB, Drujan D, Glass DJ, Frederick CB, Yoder BC, Lalush DS, et al. The ubiquitin ligase MuRF1 regulates PPARalpha activity in the heart by enhancing nuclear export via monoubiquitination. Mol Cell Endocrinol. 2015;413:36–48.CrossRef

26.

Willis MS, Wadosky KM, Rodriguez JE, Schisler JC, Lockyer P, Hilliard EG, Glass DJ, Patterson C. Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo. Cell Biochem Funct. 2014;32(1):39–50.CrossRef

27.

Parry TL, Desai G, Schisler JC, Li L, Quintana MT, Stanley N, Lockyer P, Patterson C, Willis MS. Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1. Cardiovasc Pathol. 2016;25(2):127–40.CrossRef

28.

Williams J. The decomposition of hydrogen peroxide by liver catalase. J Gen Physiol. 1928;11(4):309–37.CrossRef

29.

Wang X, Tao Y, Huang Y, Zhan K, Xue M, Wang Y, Ruan D, Liang Y, Huang X, Lin J, et al. Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1. J Cell Mol Med. 2017;21(12):3420–34.CrossRef

30.

Harris C, Wang SW, Lauchu JJ, Hansen JM. Methanol metabolism and embryotoxicity in rat and mouse conceptuses: comparisons of alcohol dehydrogenase (ADH1), formaldehyde dehydrogenase (ADH3), and catalase. Reprod Toxicol. 2003;17(3):349–57.CrossRef

31.

Praphanphoj V, Sacksteder KA, Gould SJ, Thomas GH, Geraghty MT. Identification of the alpha-aminoadipic semialdehyde dehydrogenase-phosphopantetheinyl transferase gene, the human ortholog of the yeast LYS5 gene. Mol Genet Metab. 2001;72(4):336–42.CrossRef

32.

Labrador V, Brun C, Konig S, Roatti A, Baertschi AJ. Peptidyl-glycine alpha-amidating monooxygenase targeting and shaping of atrial secretory vesicles: inhibition by mutated N-terminal ProANP and PBA. Circ Res. 2004;95(12):e98–109.CrossRef

33.

Elsayed NM, Tierney DF. Hyperoxia and xanthine dehydrogenase/oxidase activities in rat lung and heart. Arch Biochem Biophys. 1989;273(2):281–6.CrossRef

34.

Guo W, Hao B, Wang Q, Lu Y, Yue J. Requirement of B-Raf, C-Raf, and A-Raf for the growth and survival of mouse embryonic stem cells. Exp Cell Res. 2013;319(18):2801–11.CrossRef

35.

Muslin AJ. Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. Trends Cardiovasc Med. 2005;15(6):225–9.CrossRef

36.

Moritoh Y, Oka M, Yasuhara Y, Hozumi H, Iwachidow K, Fuse H, Tozawa R. Inositol Hexakisphosphate kinase 3 regulates metabolism and lifespan in mice. Sci Rep. 2016;6:32072.CrossRef

37.

Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016;7:13103.CrossRef

38.

Li HH, Du J, Fan YN, Zhang ML, Liu DP, Li L, Lockyer P, Kang EY, Patterson C, Willis MS. The ubiquitin ligase MuRF1 protects against cardiac ischemia/reperfusion injury by its proteasome-dependent degradation of phospho-c-Jun. Am J Pathol. 2011;178(3):1043–58.CrossRef

39.

Mattox TA, Young ME, Rubel CE, Spaniel C, Rodriguez JE, Grevengoed TJ, Gautel M, Xu Z, Anderson EJ, Willis MS. MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo. J Bioenerg Biomembr. 2014;46(3):173–87.CrossRef

40.

Witt SH, Granzier H, Witt CC, Labeit S. MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination. J Mol Biol. 2005;350(4):713–22.CrossRef

41.

Banerjee R, He J, Spaniel C, Quintana MT, Wang Z, Bain J, Newgard CB, Muehlbauer MJ, Willis MS. Non-targeted metabolomics analysis of cardiac muscle ring Finger-1 (MuRF1), MuRF2, and MuRF3 in vivo reveals novel and redundant metabolic changes. Metabolomics. 2015;11(2):312–22.CrossRef

42.

Frank CL, Liu F, Wijayatunge R, Song L, Biegler MT, Yang MG, Vockley CM, Safi A, Gersbach CA, Crawford GE, et al. Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum. Nat Neurosci. 2015;18(5):647–56.CrossRef

43.

Kalogeropoulos M, Varanasi SS, Olstad OK, Sanderson P, Gautvik VT, Reppe S, Francis RM, Gautvik KM, Birch MA, Datta HK. Zic1 transcription factor in bone: neural developmental protein regulates mechanotransduction in osteocytes. FASEB J. 2010;24(8):2893–903.CrossRef

44.

Mizugishi K, Aruga J, Nakata K, Mikoshiba K. Molecular properties of Zic proteins as transcriptional regulators and their relationship to GLI proteins. J Biol Chem. 2001;276(3):2180–218.CrossRef

45.

Srivastava D. Genetic assembly of the heart: implications for congenital heart disease. Annu Rev Physiol. 2001;63:451–69.CrossRef

46.

Li B, Kuriyama S, Moreno M, Mayor R. The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction. Dev. 2009;136(19):3267–78.CrossRef

47.

Makki N, Capecchi MR. Cardiovascular defects in a mouse model of HOXA1 syndrome. Hum Mol Genet. 2012;21(1):26–31.CrossRef

48.

Chen L, Ma Y, Qian L, Wang J. Sumoylation regulates nuclear localization and function of zinc finger transcription factor ZIC3. Biochim Biophys Acta. 2013;1833(12):2725–33.CrossRef

49.

Bedard JE, Purnell JD, Ware SM. Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. Hum Mol Genet. 2007;16(2):187–98.CrossRef

50.

Godfrey J, Jeanguenin L, Castro N, Olney JJ, Dudley J, Pipkin J, Walls SM, Wang W, Herr DR, Harris GL, et al. Chronic voluntary ethanol consumption induces favorable ceramide profiles in selectively bred alcohol-preferring (P) rats. PLoS One. 2015;10(9):e0139012.CrossRef

51.

Xie H, Lin XL, Zhang S, Yu L, Li XX, Huang YC, Lyu YQ, Chen HT, Xu J, Chen F. Asian J Androl. 2018;20(1):85–9. https://doi.org/10.4103/aja.aja_13_17.

52.

Zhuang LK, Wu M, Ye WJ, Liu YD. Single nucleotide polymorphisms of the DGKK gene and hypospadias in Chinese children. Zhonghua Nan Ke Xue. 2014;20(11):991–4.PubMed

53.

Ma Q, Tang Y, Lin H, Xu M, Xu G, Fang X, Chen J, Song Z, Li Z, Shi Y, et al. Diacylglycerol kinase kappa (DGKK) variants and hypospadias in Han Chinese: association and meta-analysis. BJU Int. 2015;116(4):634–40.CrossRef

54.

van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, Renkema KY, Bongers EM, Vermeulen SH, Kiemeney LA, Veltman JA, et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet. 2011;43(1):48–50.CrossRef

55.

Gaburjakova M, Bal NC, Gaburjakova J, Periasamy M. Functional interaction between calsequestrin and ryanodine receptor in the heart. Cell Mol Life Sci. 2013;70(16):2935–45.CrossRef

56.

Zarain-Herzberg A, Estrada-Aviles R, Fragoso-Medina J. Regulation of sarco (endo) plasmic reticulum Ca2+-ATPase and calsequestrin gene expression in the heart. Can J Physiol Pharmacol. 2012;90(8):1017–28.CrossRef

57.

Beard NA, Wei L, Dulhunty AF. Ca (2+) signaling in striated muscle: the elusive roles of triadin, junctin, and calsequestrin. Eur Biophys J. 2009;39(1):27–36.CrossRef

58.

Bisping E, Ikeda S, Sedej M, Wakula P, McMullen JR, Tarnavski O, Sedej S, Izumo S, Pu WT, Pieske B. Transcription factor GATA4 is activated but not required for insulin-like growth factor 1 (IGF1)-induced cardiac hypertrophy. J Biol Chem. 2012;287(13):9827–34.CrossRef

59.

Rachmin I, Tshori S, Smith Y, Oppenheim A, Marchetto S, Kay G, Foo RS, Dagan N, Golomb E, Gilon D, et al. Erbin is a negative modulator of cardiac hypertrophy. Proc Natl Acad Sci U S A. 2014;111(16):5902–7.CrossRef

60.

Vande Perre P, Zazo Seco C, Patat O, Bouneau L, Vigouroux A, Bourgeois D, El Hout S, Chassaing N, Calvas P. Eur J Med Genet. 2018;61(2):72–8.

61.

Mora C, Serzanti M, Giacomelli A, Beltramone S, Marchina E, Bertini V, Piovani G, Refsgaard L, Olesen MS, Cortellini V, et al. Generation of induced pluripotent stem cells (iPSC) from an atrial fibrillation patient carrying a PITX2 p.M200V mutation. Stem Cell Res. 2017;24:8–11.CrossRef

62.

Weng LC, Lunetta KL, Muller-Nurasyid M, Smith AV, Theriault S, Weeke PE, Barnard J, Bis JC, Lyytikainen LP, Kleber ME, et al. Genetic interactions with age, sex, body mass index, and hypertension in relation to atrial fibrillation: the AFGen consortium. Sci Rep. 2017;7(1):11303.CrossRef

63.

Ocana OH, Coskun H, Minguillon C, Murawala P, Tanaka EM, Galceran J, Munoz-Chapuli R, Nieto MA. A right-handed signalling pathway drives heart looping in vertebrates. Nature. 2017;549(7670):86–90.CrossRef

64.

Lee JY, Kim TH, Yang PS, Lim HE, Choi EK, Shim J, Shin E, Uhm JS, Kim JS, Joung B, et al. Korean atrial fibrillation network genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci. Eur Heart J. 2017;38(34):2586–94.CrossRef

65.

Chen L, Yang F, Chen X, Rao M, Zhang NN, Chen K, Deng H, Song JP, Hu SS. Comprehensive myocardial Proteogenomics profiling reveals C/EBPalpha as the key factor in the lipid storage of ARVC. J Proteome Res. 2017;16(8):2863–76.CrossRef

66.

Capitanio D, Fania C, Torretta E, Vigano A, Moriggi M, Bravata V, Caretti A, Levett DZH, Grocott MPW, Samaja M, et al. TCA cycle rewiring fosters metabolic adaptation to oxygen restriction in skeletal muscle from rodents and humans. Sci Rep. 2017;7(1):9723.CrossRef

67.

Sun W, Kato H, Kitajima S, Lee KL, Gradin K, Okamoto T, Poelllinger L. Interaction between von Hippel-Lindau protein and fatty acid synthase modulates hypoxia target gene expression. Sci Rep. 2017;7(1):7190.CrossRef

68.

Lee HJ, Jung YH, Choi GE, Ko SH, Lee SJ, Lee SH, Han HJ. BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol. 2017;13:426–43.CrossRef

69.

Ma L, Yang J, Runesha HB, Tanaka T, Ferrucci L, Bandinelli S, Da Y. Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham heart study data. BMC Med Genet. 2010;11:55.CrossRef

70.

Huertas-Vazquez A, Nelson CP, Guo X, Reinier K, Uy-Evanado A, Teodorescu C, Ayala J, Jerger K, Chugh H, Wtccc, et al. Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease. PLoS One. 2013;8(4):e59905.

Title: Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice
Authors: Robert H. Oakley
Matthew J. Campen
Michael L. Paffett
Xin Chen
Zhongjing Wang
Traci L. Parry
Carolyn Hillhouse
John A. Cidlowski
Monte S. Willis
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0670-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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