Abstract
Myocardial hypertrophy is a common precursor of many diseases, and it can lead to myocardial ischemia and weaken cardiac contractility. High-sugar diets and diabetes are high risk factors for cardiac hypertrophy. O-GlcNAcylation, a dynamic and ubiquitous post-translational glycosylation of proteins on serine/threonine residues, has been usually considered as a nutrient sensor. Hyperglycemia, hyperlipidemia, and hyperinsulinemia lead to an enhancement of protein O-GlcNAcylation; however, whether excessive O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of proteins in cardiomyocytes causes cardiac hypertrophy remains unclear. In this study, we treated cultured primary cardiomyocytes or mice with streptozotocin (STZ) or PUGNAc, two inhibitors of O-GlcNAcase (OGA) to elevate cellular O-GlcNAcylation. We found that increased O-GlcNAcylation induced hypertrophy-like changes by detecting cardiomyocyte morphology or measuring the thickness of mice left ventricular wall with HE staining. The mRNA levels of cardiac hypertrophy–related genes, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), are increased in drug treatment groups. We further found that the increase of O-GlcNAcylation upregulated the activity of cAMP response element-binding protein (CREB) in cultured primary cells and in vivo by detecting the phosphorylation level of CREB by Western blot and the mRNA levels of CREB downstream targets C-fos and C-jun by RT-qPCR. These results suggest that the increased O-GlcNAcylation in cardiomyocytes is associated with cardiac hypertrophy both in cultured cells and in vivo, which provides possible intervention targets and approaches for the clinical treatment of myocardial hypertrophy triggered by high carbohydrate diets.
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References
Biswas A, Das S, Kapoor M, Shamsudheen KV, Jayarajan R, Verma A, Seth S, Bhargava B, Scaria V, Sivasubbu S, Rao VR (2018) Familial hypertrophic cardiomyopathy - identification of cause and risk stratification through exome sequencing. Gene 660:151–156
Butler TJ, Ashford D, Seymour AM (2017) Western diet increases cardiac ceramide content in healthy and hypertrophied hearts. Nutr Metab Cardiovasc Dis 27:991–998
Comer FI, Hart GW (2000) O-glycosylation of nuclear and cytosolic proteins. Dynamic interplay between O-GlcNAc and O-phosphate J Biol Chem 275:29179–29182
Dadson K, Hauck L, Billia F (2017) Molecular mechanisms in cardiomyopathy. Clin Sci (Lond) 131:1375–1392
Gudi T, Lohmann SM, Pilz RB (1997) Regulation of gene expression by cyclic GMP-dependent protein kinase requires nuclear translocation of the kinase: identification of a nuclear localization signal. Mol Cell Biol 17:5244–5254
Hart GW (1997) Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem 66:315–335
Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022
Kuhn M (2015) Cardiac actions of atrial natriuretic peptide: new visions of an old friend. Circ Res 116:1278–1280
Lamarre-Vincent N, Hsieh-Wilson LC (2003) Dynamic glycosylation of the transcription factor CREB: a potential role in gene regulation. J Am Chem Soc 125:6612–6613
Le Corvoisier P, Adamy C, Sambin L, Crozatier B, Berdeaux A, Michel JB, Hittinger L, Su J (2010) The cardiac renin-angiotensin system is responsible for high-salt diet-induced left ventricular hypertrophy in mice. Eur J Heart Fail 12:1171–1178
Lefebvre T, Dehennaut V, Guinez C, Olivier S, Drougat L, Mir AM, Mortuaire M, Vercoutter-Edouart AS, Michalski JC (2010) Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer’s disease. Biochim Biophys Acta 1800:67–79
Liu J, Pang Y, Chang T, Bounelis P, Chatham JC, Marchase RB (2006) Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia. J Mol Cell Cardiol 40:303–312
Lopes LR, Brito D, Belo A, Cardim N, Portuguese Registry of Hypertrophic C (2019) Genetic characterization and genotype-phenotype associations in a large cohort of patients with hypertrophic cardiomyopathy - an ancillary study of the Portuguese registry of hypertrophic cardiomyopathy. Int J Cardiol 278:173–179
Marian AJ, Braunwald E (2017) Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 121:749–770
Marsh SA, Collins HE, Chatham JC (2014) Protein O-GlcNAcylation and cardiovascular (patho)physiology. J Biol Chem 289:34449–34456
Ortega-Loubon C, Fernandez-Molina M, Singh G, Correa R (2019) Obesity and its cardiovascular effects. Diabetes Metab Res Rev 35:e3135. https://doi.org/10.1002/dmrr.3135:e3135
Ozgen N, Obreztchikova M, Guo J, Elouardighi H, Dorn GW 2nd, Wilson BA, Steinberg SF (2008) Protein kinase D links Gq-coupled receptors to cAMP response element-binding protein (CREB)-Ser133 phosphorylation in the heart. J Biol Chem 283:17009–17019
Pilz RB, Casteel DE (2003) Regulation of gene expression by cyclic GMP. Circ Res 93:1034–1046
Rexach JE, Clark PM, Mason DE, Neve RL, Peters EC, Hsieh-Wilson LC (2012) Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Nat Chem Biol 8:253–261
Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, Pagano F, Schiavon S, Bordin A, Carrizzo A, Vecchione C, Valenti V, Chimenti I, De Falco E, Sciarretta S, Frati G (2017) A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxidative Med Cell Longev 2017:3920195
Schunkert H, Jahn L, Izumo S, Apstein CS, Lorell BH (1991) Localization and regulation of c-fos and c-jun protooncogene induction by systolic wall stress in normal and hypertrophied rat hearts. Proc Natl Acad Sci U S A 88:11480–11484
Schwartz K, Carrier L, Lompre AM, Mercadier JJ, Boheler KR (1992) Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart. Basic Res Cardiol 87(Suppl 1):285–290
Seferovic PM, Paulus WJ (2015) Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 36:1718-1727, 1727a-1727c
Shimizu I, Minamino T (2016) Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 97:245–262
Song W, Wang H, Wu Q (2015) Atrial natriuretic peptide in cardiovascular biology and disease (NPPA). Gene 569:1–6
Swynghedauw B (1986) Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev 66:710–771
Thiel G, Rossler OG (2017) Resveratrol regulates gene transcription via activation of stimulus-responsive transcription factors. Pharmacol Res 117:166–176
van der Velden J, Tocchetti CG, Varricchi G, Bianco A, Sequeira V, Hilfiker-Kleiner D, Hamdani N, Leite-Moreira AF, Mayr M, Falcao-Pires I, Thum T, Dawson DK, Balligand JL, Heymans S (2018) Metabolic changes in hypertrophic cardiomyopathies: scientific update from the working group of myocardial function of the European Society of Cardiology. Cardiovasc Res 114:1273–1280
Wang D, Gladysheva IP, Fan TH, Sullivan R, Houng AK, Reed GL (2014) Atrial natriuretic peptide affects cardiac remodeling, function, heart failure, and survival in a mouse model of dilated cardiomyopathy. Hypertension 63:514–519
Watson LJ, Long BW, DeMartino AM, Brittian KR, Readnower RD, Brainard RE, Cummins TD, Annamalai L, Hill BG, Jones SP (2014) Cardiomyocyte Ogt is essential for postnatal viability. Am J Physiol Heart Circ Physiol 306:H142–H153
Wells L, Vosseller K, Hart GW (2001) Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 291:2376–2378
Xie S, Jin N, Gu J, Shi J, Sun J, Chu D, Zhang L, Dai CL, Gu JH, Gong CX, Iqbal K, Liu F (2016) O-GlcNAcylation of protein kinase a catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer’s disease. Aging Cell 15:455–464
Zeng H, Vaka VR, He X, Booz GW, Chen JX (2015) High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss. J Cell Mol Med 19:1847–1856
Funding
This study was supported by Nantong Youth Medical Talents Support Program, Nantong 226 High-level Talents Training Project, the Science Foundation of Nantong City (Grant No. YYZ16022) and Health Research grant of Nantong Commission of Health (Grant No. 2020JCC048).
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XC and LS were involved in study design, experiments, and data interpretation and manufactured the figures. LZ, YS, and QS performed experiments and analysis. LS and HH reviewed and wrote the manuscript. All authors have read and approved the final manuscript.
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Editor: Tetsuji Okamoto
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Chen, X., Zhang, L., He, H. et al. Increased O-GlcNAcylation induces myocardial hypertrophy. In Vitro Cell.Dev.Biol.-Animal 56, 735–743 (2020). https://doi.org/10.1007/s11626-020-00503-z
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DOI: https://doi.org/10.1007/s11626-020-00503-z