Skip to main content
SpringerLink
Log in

Role of Sirtuins in Regulation of Cardiac Adaptation Associated with Hypertrophy

  • Chapter
  • First Online:
Cardiac Adaptations

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 4))

  • 1830 Accesses

Abstract

Lysine-acetylation within a protein is considered as a functionally relevant post-translation modification regulating activity of the target protein. While protein acetylation is regulated by acetyl-transferases, deacetylation is catalyzed by deacetylases. Recently a family of nicotinamide-adenine-dinucleotide (NAD)-dependent deacetylases, called sirtuins, has been identified, which are emerging as key regulators of many biological functions, spanning from cell growth to longevity. Among the seven sirtuin isoforms (SIRT1–SIRT7) expressed in mammalian cells, two isoforms SIRT1 and SIRT3 have been studied with some detail for their roles in regulating cardiac adaptation to increased workload. SIRT1 was found to regulate Akt signaling and plays an essential role for the development of cardiac hypertrophy. SIRT3 on the other hand was found to act as a negative regulator of cardiac hypertrophy, which also protects cardiomyocytes from oxidative stress-mediated apoptosis. The mechanism behind anti-growth and anti-apoptotic activity of SIRT3 seems to stem from its ability to deacetylate several mitochondrial target proteins and thereby promoting overall function of mitochondria to generate less reactive oxygen species (ROS) and more ATP synthesis. As both SIRT1 and SIRT3 are activated by physical exercise and calorie restriction, some of the cardiac benefits arising from these interventions are likely to be stemming from the activation of these two molecules. This chapter gives a brief overview of sirtuin biology and then focuses on the opposite roles of SIRT1 and SIRT3 to regulate cardiac remodeling associated with hypertrophy.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lloyd-Jones D, Adams R, Carnethon M et al (2009) Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:e21–e181

    Article  PubMed  Google Scholar 

  2. Rosamond W, Flegal K, Furie K et al (2008) Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:e25–e146

    Article  PubMed  Google Scholar 

  3. Ingram DK, Anson RM, de Cabo R et al (2004) Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci 1019:412–423

    Article  PubMed  CAS  Google Scholar 

  4. Sinclair DA (2005) Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 126:987–1002

    Article  PubMed  CAS  Google Scholar 

  5. Marzetti E, Wohlgemuth SE, Anton SD et al (2009) Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives. Clin Geriatr Med 25:715–732, ix

    Google Scholar 

  6. Finkel T, Deng C-X, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460:587–591

    Google Scholar 

  7. Lin S, Ford E, Haigis M et al (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18:12–16

    Article  PubMed  CAS  Google Scholar 

  8. Haigis M, Guarente LP (2006) Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921

    Article  PubMed  CAS  Google Scholar 

  9. Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273:793–798

    Article  PubMed  CAS  Google Scholar 

  10. Sundaresan N, Pillai VB, Samant S, et al (2011) The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal 4(182):ra46–ra58

    Google Scholar 

  11. Li X, Zhang S, Blander G et al (2007) SIRT1 deacetylases and positively regulates the nuclear receptor LXR. Mol Cell 28:91–106

    Article  PubMed  Google Scholar 

  12. Liu Y, Dentin R, Chen D et al (2008) A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456:269–273

    Article  PubMed  CAS  Google Scholar 

  13. Motta MC, Divecha N, Lemieux M et al (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116:551–563

    Article  PubMed  CAS  Google Scholar 

  14. Rodgers JT, Puigserver P (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci 104:12861–12866

    Article  PubMed  CAS  Google Scholar 

  15. Tanno M, Sakamoto J, Miura T et al (2007) Nucleocytoplasmic Shuttling of the NAD+-dependent Histone Deacetylase SIRT1. J Biol Chem 282:6823–6832

    Article  PubMed  CAS  Google Scholar 

  16. Vaziri H, Dessain SK, Ng Eaton E et al (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159

    Article  PubMed  CAS  Google Scholar 

  17. Inoue T, Hiratsuka M, Osaki M et al (2006) SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 26:945–995

    Article  PubMed  Google Scholar 

  18. Huang JY, Hirschey MD, Shimazu T et al (2010) Mitochondrial sirtuins. Biochim Biophys Acta 1804:1645–1651

    Article  PubMed  CAS  Google Scholar 

  19. Kawahara TL, Michishita E, Adler AS et al (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136:62–74

    Article  PubMed  CAS  Google Scholar 

  20. Vakhrusheva O, Smolka C, Gajawada P et al (2008) SIRT7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res 102:703–710

    Article  PubMed  CAS  Google Scholar 

  21. Michishita E, Park JY, Burneskis JM et al (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16:4623–4635

    Article  PubMed  CAS  Google Scholar 

  22. Nasrin N, Kaushik VK, Fortier E et al (2009) JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One 4:e8414

    Article  PubMed  Google Scholar 

  23. Alcendor RR, Kirshenbaum LA, Ima S et al (2004) Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95:971–980

    Article  PubMed  CAS  Google Scholar 

  24. Li L, Zhao L, Yi-Ming W et al (2009) Sirt1 hyper expression in SHR heart related to left ventricular hypertrophy. Can J Physiol Pharmacol 87:56–62

    Article  PubMed  Google Scholar 

  25. Vahtola E, Louhelainen M, Merasto S et al (2008) Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat. J Hypertens 26:334–344

    Article  PubMed  CAS  Google Scholar 

  26. Alcendor RR, Gao S, Zhai P et al (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100:1512–1521

    Article  PubMed  CAS  Google Scholar 

  27. Hsu CP, Zhai P, Yamamoto T et al (2010) Silent Information Regulator 1 protects the heart from ischemia/reperfusion. Circulation 122:2170–2182

    Article  PubMed  Google Scholar 

  28. McBurney MW, Yang X, Jardine K et al (2003) The mammalian SIR2 alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 23:38–54

    Article  PubMed  CAS  Google Scholar 

  29. Cheng HL, Mostoslavsky R, Saito S et al (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA. 100:10794–10799

    Article  PubMed  CAS  Google Scholar 

  30. Coussens M, Maresh JG, Yanagimachi R et al (2008) SIRT1 deficiency attenuates spermatogenesis and germ cell function. PLoS One 3:e1571

    Article  PubMed  Google Scholar 

  31. Sundaresan NR, Gupta M, Kim G et al (2009) SIRT3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758–27571

    PubMed  CAS  Google Scholar 

  32. Hallows WC, Albaugh BN, Denu JM (2008) Where in the cell is SIRT3?–functional localization of an NAD+-dependent protein deacetylase. Biochem J 411:e11–e13

    Article  PubMed  CAS  Google Scholar 

  33. Schwer B, North BJ, Frye RA et al (2002) The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 158:647–657

    Article  PubMed  CAS  Google Scholar 

  34. Onyango P, Celic I, McCaffery JM et al (2002) SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci USA 99:13653–13658

    Article  PubMed  CAS  Google Scholar 

  35. Nakamura Y, Ogura M, Tanaka D, Inagaki N (2008) Localization of mouse mitochondrial SIRT proteins: shift of SIRT3 to nucleus by co-expression with SIRT5. Biochem Biophys Res Commun 366:174–179

    Article  PubMed  CAS  Google Scholar 

  36. Scher MB, Vaquero A, Reinberg D (2007) SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev 21:920–928

    Article  PubMed  CAS  Google Scholar 

  37. Cooper HM, Spelbrink JN (2008) The human SIRT3 protein deacetylase is exclusively mitochondrial. Biochem J 411:279–285

    Article  PubMed  CAS  Google Scholar 

  38. Cooper HM, Huang JY, Verdin E, Spelbrink JN (2009) A new splice variant of the mouse SIRT3 gene encodes the mitochondrial precursor protein. PLoS One 4:e4986

    Article  PubMed  Google Scholar 

  39. Yang Y, Chen KY, Tong Q (2011) Murine SIRT3 protein isoforms have variable half-lives. Gene 488:46–51

    Article  PubMed  CAS  Google Scholar 

  40. Yang Y, Hubbard BP, Sinclair DA, Tong Q (2010) Characterization of murine SIRT3 transcript variants and corresponding protein products. J Cell Biochem 111:1051–1058

    Article  PubMed  CAS  Google Scholar 

  41. Sundaresan NR, Samant SA, Pillai VB et al (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 28:6384–6401

    Article  PubMed  CAS  Google Scholar 

  42. Taegtmeyer H (2000) Metabolism–the lost child of cardiology. J Am Coll Cardiol 36:1386–1388

    Article  PubMed  CAS  Google Scholar 

  43. Leong HS, Brownsey RW, Kulpa JE, Allard MF (2003) Glycolysis and pyruvate oxidation in cardiac hypertrophy–why so unbalanced? Comp Biochem Physiol A Mol Integr Physiol 135:499–513

    Article  PubMed  CAS  Google Scholar 

  44. Huss JM, Kelly DP (2005) Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 115:547–555

    PubMed  CAS  Google Scholar 

  45. Finck BN, Lehman JJ, Leone TC et al (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130

    PubMed  CAS  Google Scholar 

  46. Hirschey MD, Shimazu T, Goetzman E et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125

    Article  PubMed  CAS  Google Scholar 

  47. Hallows WC, Yu W, Smith BC et al (2011) SIRT3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 41:139–149

    Article  PubMed  CAS  Google Scholar 

  48. Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81:412–419

    Article  PubMed  CAS  Google Scholar 

  49. Pillai VB, Sundaresan NR, Kim G et al (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 285:3133–3144

    Article  PubMed  CAS  Google Scholar 

  50. Ahn BH, Kim HS, Song S et al (2008) A role for the mitochondrial deacetylase SIRT3 in regulating energy homeostasis. Proc Natl Acad Sci USA 105:14447–14452

    Article  PubMed  CAS  Google Scholar 

  51. Fujino T, Kondo J, Ishikawa M et al (2001) Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J Biol Chem 276:11420–11426

    Article  PubMed  CAS  Google Scholar 

  52. Schwer B, Bunkenborg J, Verdin RO et al (2006) Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci USA 103:10224–10229

    Article  PubMed  CAS  Google Scholar 

  53. Schlicker C, Gertz M, Papatheodorou P et al (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins SIRT3 and SIRT5. J Mol Biol 382:790–801

    Article  PubMed  CAS  Google Scholar 

  54. Cimen H, Han MJ, Yang YT et al (2010) Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49:304–311

    Article  PubMed  CAS  Google Scholar 

  55. Kim HS, Patel K, Muldoon-Jacobs K et al (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17:41–52

    Article  PubMed  CAS  Google Scholar 

  56. Shulga N, Wilson-Smith R, Pastorino JG (2010) Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. J Cell Sci 123:894–902

    Article  PubMed  CAS  Google Scholar 

  57. Hafner AV, Dai J, Gomes AP, et al (2011) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2:914–923

    Google Scholar 

  58. Palacios OM, Carmona JJ, Michan S et al (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY) 1:771–783

    CAS  Google Scholar 

  59. Shi T, Fan GQ, Xiao SD (2010) SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells. J Dig Dis 11:55–62

    Article  PubMed  CAS  Google Scholar 

  60. Dyck JRB, Lopaschuk GD (2006) AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol 574:95–112

    Article  PubMed  CAS  Google Scholar 

  61. Chan AYM, Dolinsky VW, Soltys C-LM (2008) Resveratrol Inhibits Cardiac Hypertrophy via AMP-activated Protein Kinase and Akt. J Biol Chem 283:24194–24201

    Article  PubMed  CAS  Google Scholar 

  62. Meng RS, Pei ZH, Yin R et al (2009) Adenosine monophosphate-activated protein kinase inhibits cardiac hypertrophy through reactivating peroxisome proliferator-activated receptor-alpha signaling pathway. Eur J Pharmacol 620:63–70

    Article  PubMed  CAS  Google Scholar 

  63. Ikeda Y, Sato K, Pimentel DR et al (2009) Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J Biol Chem 284:35839–35849

    Article  PubMed  CAS  Google Scholar 

  64. Lanza IR, Nair KS (2010) Mitochondrial function as a determinant of life span. Pflugers Arch 459:277–289

    Article  PubMed  CAS  Google Scholar 

  65. Li M, Chiu J-F, Mossman BT, Fukagawa NK (2006) Down-regulation of manganese-superoxide dismutase through phosphorylation of FOXO3a by Akt in explanted vascular smooth muscle cells from old rats. J Biol Chem 281:40429–40439

    Article  PubMed  CAS  Google Scholar 

  66. Tan W-Q, Wang K, Lv D-Y, Li P-F (2008) Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase. J Biol Chem 283:29730–29739

    Article  PubMed  CAS  Google Scholar 

  67. Lang D (2002) Cardiac hypertrophy and oxidative stress: a leap of faith or stark reality? Heart 87:316–317

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from AHA and NIH.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Chicago, 5841 South Maryland Avenue, Chicago, IL, 60637, USA

    Vinodkumar B. Pillai & Mahesh P. Gupta

Authors
  1. Vinodkumar B. Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahesh P. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahesh P. Gupta .

Editor information

Editors and Affiliations

  1. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

  2. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pillai, V.B., Gupta, M.P. (2013). Role of Sirtuins in Regulation of Cardiac Adaptation Associated with Hypertrophy. In: Ostadal, B., Dhalla, N. (eds) Cardiac Adaptations. Advances in Biochemistry in Health and Disease, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5203-4_19

Download citation

Publish with us

Policies and ethics

Search

Navigation