Skip to main content
SpringerLink
Log in

Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Patients with diabetes have a much greater risk of developing heart failure than non-diabetic patients, particularly in response to an additional hemodynamic stress such as hypertension or infarction. Previous studies have shown that increased glucose metabolism via the hexosamine biosynthesis pathway (HBP) and associated increase in O-linked-β-N-acetylglucosamine (O-GlcNAc) levels on proteins contributed to the adverse effects of diabetes on the heart. Therefore, in this study we tested the hypothesis that diabetes leads to impaired cardiomyocyte hypertrophic and cell signaling pathways due to increased HBP flux and O-GlcNAc modification on proteins. Cardiomyocytes isolated from type 2 diabetic db/db mice and non-diabetic controls were treated with 1 μM ANG angiotensin II (ANG) and 10 μM phenylephrine (PE) for 24 h. Activation of hypertrophic and cell signaling pathways was determined by assessing protein expression levels of atrial natriuretic peptide (ANP), α-sarcomeric actin, p53, Bax and Bcl-2 and phosphorylation of p38, ERK and Akt. ANG II and PE significantly increased levels of ANP and α-actin and phosphorylation of p38 and ERK in the non-diabetic but not in the diabetic group; phosphorylation of Akt was unchanged irrespective of group or treatment. Constitutive Bcl-2 levels were lower in diabetic hearts, while there was no difference in p53 and Bax. Activation of the HBP and increased protein O-GlcNAcylation in non-diabetic cardiomyocytes exhibited a significantly decreased hypertrophic signaling response to ANG or PE compared to control cells. Inhibition of the HBP partially restored the hypertrophic signaling response of diabetic cardiomyocytes. These results suggest that activation of the HBP and protein O-GlcNAcylation modulates hypertrophic and cell signaling pathways in type 2 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223

    Article  PubMed  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  • Champattanachai V, Marchase RB, Chatham JC (2007) Glucosamine protects neonatal cardiomyocytes from ischemia–reperfusion injury via increased protein-associated O-GlcNAc. Am J Physiol Cell Physiol 292:C178–C187

    Article  CAS  PubMed  Google Scholar 

  • Chatham JC, Marchase RB (2010) The role of protein O-linked beta-N-acetylglucosamine in mediating cardiac stress responses. Biochim Biophys Acta 1800:57–66

    Google Scholar 

  • Chatham JC, Forder JR, McNeill JH (eds) (1996) The Heart in Diabetes. Kluwer Academic Publishers, Norwell

    Google Scholar 

  • Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278:44230–44237

    Article  CAS  PubMed  Google Scholar 

  • Copeland RJ, Bullen JW, Hart GW (2008) Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. Am J Physiol Endocrinol Metab 295:E17–E28

    Article  CAS  PubMed  Google Scholar 

  • Davidoff AJ (2006) Convergence of glucose- and fatty acid-induced abnormal myocardial excitation–contraction coupling and insulin signalling. Clin Exp Pharmacol Physiol 33:152–158

    Article  CAS  PubMed  Google Scholar 

  • Davidoff AJ, Davidson MB, Carmody MW, Davis ME, Ren J (2004) Diabetic cardiomyocyte dysfunction and myocyte insulin resistance: role of glucose-induced PKC activity. Mol Cell Biochem 262:155–163

    Article  CAS  PubMed  Google Scholar 

  • Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV (2000) Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 101:2271–2276

    CAS  PubMed  Google Scholar 

  • Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97:12222–12226

    Article  CAS  PubMed  Google Scholar 

  • Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139

    Article  CAS  PubMed  Google Scholar 

  • Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J (2001) Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50:2363–2375

    Article  CAS  PubMed  Google Scholar 

  • Fulop N, Marchase RB, Chatham JC (2007a) Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc Res 73:288–297

    Article  PubMed  Google Scholar 

  • Fulop N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC (2007b) The impact of type-2 diabetes and aging on cardiomyocyte function and O-Linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol 292:C1370–C1378

    Article  CAS  PubMed  Google Scholar 

  • Fulop N, Zhang Z, Marchase RB, Chatham JC (2007c) Glucosamine cardioprotection in perfused rat heart associated with increased O-Linked N-acetylglucosamine protein modification and altered p38 activation. Am J Physiol Heart Circ Physiol 292:H2227–H2236

    Article  CAS  PubMed  Google Scholar 

  • Galderisi M, Anderson KM, Wilson PWF, Levy D (1991) Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (The Framingham Heart Study). Am J Cardiol 68:85–89

    Article  CAS  PubMed  Google Scholar 

  • Garcia MJ, McNamara PM, Gordon T, Kannell WB (1974) Morbidity and mortality in diabetics in the Framingham population. Diabetes 23:105–111

    CAS  PubMed  Google Scholar 

  • Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559

    Article  CAS  PubMed  Google Scholar 

  • Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022

    Article  CAS  PubMed  Google Scholar 

  • Hayat SA, Patel B, Khattar RS, Malik RA (2004) Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin Sci (Lond) 107:539–557

    Article  CAS  Google Scholar 

  • Heyliger CE, Pierce GN, Singal PK, Beamish RE, Dhalla NS (1982) Cardiac alpha- and beta-adrenergic receptor alterations in diabetic cardiomyopathy. Basic Res Cardiol 77:610–618

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Belke D, Suarez J, Swanson E, Clark R, Hoshijima M, Dillmann WH (2005) Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res 96:1006–1013

    Article  CAS  PubMed  Google Scholar 

  • Hunton DL, Lucchesi PA, Pang Y, Cheng X, Dell’Italia LJ, Marchase RB (2002) Capacitative calcium entry contributes to nuclear factor of activated T-cells nuclear translocation and hypertrophy in cardiomyocytes. J Biol Chem 277:14266–14273

    Article  CAS  PubMed  Google Scholar 

  • Hunton DL, Zou LY, Pang Y, Marchase RB (2004) Adult rat cardiomyocytes exhibit capacitative calcium entry. Am J Physiol Heart Circ Physiol 286:H1124–H1132

    Article  CAS  PubMed  Google Scholar 

  • Jones SP, Zachara NE, Ngoh GA, Hill BG, Teshima Y, Bhatnagar A, Hart GW, Marban E (2008) Cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation 117:1172–1182

    Article  CAS  PubMed  Google Scholar 

  • Kang JG, Park SY, Ji S, Jang I, Park S, Kim HS, Kim SM, Yook JI, Park YI, Roth J, Cho JW (2009) O-GlcNAc protein modification in cancer cells increases in response to glucose deprivation through glycogen degradation. J Biol Chem 284:34777–34784

    Article  CAS  PubMed  Google Scholar 

  • Laczy B, Hill BG, Wang K, Paterson AJ, White CR, Xing D, Chen YF, Darley-Usmar V, Oparil S, Chatham JC (2009) Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system. Am J Physiol Heart Circ Physiol 296:H13–H28

    Article  CAS  PubMed  Google Scholar 

  • Liu K, Paterson AJ, Chin E, Kudlow JE (2000) Glucose stimulates protein modification by O-linked GlcNAc in pancreatic beta cells: linkage of O-linked GlcNAc to beta cell death. Proc Natl Acad Sci USA 97:2820–2825

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Marchase RB, Chatham JC (2007) Increased O-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis. Am J Physiol Heart Circ Physiol 293:H1391–H1399

    Article  CAS  PubMed  Google Scholar 

  • Love DC, Hanover JA (2005) The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci STKE 312:re13

    Google Scholar 

  • Marsh SA, Dell’italia LJ, Chatham JC (2009) Interaction of diet and diabetes on cardiovascular function in rats. Am J Physiol Heart Circ Physiol 296:H282–H292

    Article  CAS  PubMed  Google Scholar 

  • Nagy T, Champattanachai V, Marchase RB, Chatham JC (2006) Glucosamine inhibits angiotensin II induced cytoplasmic Ca2+ elevation in neonatal cardiomyocytes via protein-associated O-GlcNAc. Am J Physiol Cell Physiol 290:C57–C65

    Article  CAS  PubMed  Google Scholar 

  • Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471

    Article  CAS  PubMed  Google Scholar 

  • O’Connell TD, Ni YG, Lin K-M, Han H, Yan X (2003) Isolation and culture of adult mouse cardiac myocytes for signaling studies. AfCS Research Reports 1 (online)

  • Ohba T, Watanabe H, Murakami M, Takahashi Y, Iino K, Kuromitsu S, Mori Y, Ono K, Iijima T, Ito H (2007) Upregulation of TRPC1 in the development of cardiac hypertrophy. J Mol Cell Cardiol 42:498–507

    Article  CAS  PubMed  Google Scholar 

  • Pang Y, Hunton DL, Bounelis P, Marchase RB (2002) Hyperglycemia inhibits capacitative calcium entry and hypertrophy in neonatal cardiomyocytes. Diabetes 51:3461–3467

    Article  CAS  PubMed  Google Scholar 

  • Pang Y, Bounelis P, Chatham JC, Marchase RB (2004) The hexosamine pathway is responsible for the inhibition by diabetes of phenylephrine-induced inotropy. Diabetes 53:1074–1081

    Article  CAS  PubMed  Google Scholar 

  • Petrova R, Yamamoto Y, Muraki K, Yonekura H, Sakurai S, Watanabe T, Li H, Takeuchi M, Makita Z, Kato I, Takasawa S, Okamoto H, Imaizumi Y, Yamamoto H (2002) Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol 34:1425–1431

    Article  CAS  PubMed  Google Scholar 

  • Poornima IG, Parikh P, Shannon RP (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98:596–605

    Article  CAS  PubMed  Google Scholar 

  • Preis SR, Hwang SJ, Coady S, Pencina MJ, D’Agostino RB Sr, Savage PJ, Levy D, Fox CS (2009) Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005. Circulation 119:1728–1735

    Article  PubMed  Google Scholar 

  • Ren J, Gintant GA, Miller RE, Davidoff AJ (1997) High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner. Am J Physiol Heart Circ Physiol 273:H2876–H2883

    CAS  Google Scholar 

  • Ren J, Dong F, Cai GJ, Zhao P, Nunn JM, Wold LE, Pei J (2010) Interaction between age and obesity on cardiomyocyte contractile function: role of leptin and stress signaling. PLoS One 5:e10085

    Article  PubMed  Google Scholar 

  • Rodrigues B, McNeill JH (1992) The diabetic heart: metabolic causes for the development of a cardiomyopathy. Cardiovasc Res 26:913–922

    Article  CAS  PubMed  Google Scholar 

  • Rosenkranz AC, Hood SG, Woods RL, Dusting GJ, Ritchie RH (2003) B-type natriuretic peptide prevents acute hypertrophic responses in the diabetic rat heart: importance of cyclic GMP. Diabetes 52:2389–2395

    Article  CAS  PubMed  Google Scholar 

  • Shan D, Marchase RB, Chatham JC (2008) Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia–reperfusion in adult mouse cardiomyocytes. Am J Physiol Cell Physiol 294:C833–C841

    Article  CAS  PubMed  Google Scholar 

  • Shiojima I, Walsh K (2006) Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 20:3347–3365

    Article  CAS  PubMed  Google Scholar 

  • Slawson C, Housley MP, Hart GW (2006) O-GlcNAc cycling: how a single sugar post-translational modification is changing the way we think about signaling networks. J Cell Biochem 97:71–83

    Article  CAS  PubMed  Google Scholar 

  • Tanaka Y, Kashiwagi A, Saeki Y, Shigeta Y (1992) Abnormalities in cardiac alpha 1-adrenoceptor and its signal transduction in streptozocin-induced diabetic rats. Am J Physiol 263:E425–E429

    CAS  PubMed  Google Scholar 

  • Taylor RP, Parker GJ, Hazel MW, Soesanto Y, Fuller W, Yazzie MJ, McClain DA (2008) Glucose deprivation stimulates O-GlcNAc modification of proteins through up-regulation of O-linked N-acetylglucosaminyltransferase. J Biol Chem 283:6050–6057

    Article  CAS  PubMed  Google Scholar 

  • Teo CF, Ingale S, Wolfert MA, Elsayed GA, Not LG, Chatham JC, Wells L, Boons GJ (2010) Glycopeptide-specific monoclonal antibodies suggest new roles for O-GlcNAc. Nat Chem Biol 6:338–343

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Chatham JC (2004) The onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function following ischemia in the isolated perfused heart. Am J Physiol Endocrin Met 286:E725–E736

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institute of Health grants (HL-77100, HL-67464, HL-101192). We are grateful for the technical support provided by Charlye A. Brocks and Dan Shan.

Author information

Author notes

  1. Susan A. Marsh

    Present address: Program in Nutrition and Exercise Physiology, Washington State University, Spokane, WA, USA

Authors and Affiliations

  1. Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, 302 Ziegler Research Building, Birmingham, AL, 35294-0007, USA

    Susan A. Marsh, Louis J. Dell’Italia & John C. Chatham

Authors
  1. Susan A. Marsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Louis J. Dell’Italia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John C. Chatham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John C. Chatham.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marsh, S.A., Dell’Italia, L.J. & Chatham, J.C. Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids 40, 819–828 (2011). https://doi.org/10.1007/s00726-010-0699-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-010-0699-8

Keywords

Search

Navigation