Skip to main content
SpringerLink
Log in

Integrins: Implications for Aging in Heart Failure Therapy

  • Chapter
  • First Online:
Book cover Aging and Heart Failure

Abstract

Integrins are a large family of heterodimeric transmembrane receptors that attach cells to extracellular matrix proteins of the basement membrane. They are bidirectional signaling molecules composed of noncovalently associated α and β subunits. They can form over 24 pairs in mammalian cells creating a wide range of ligand specificity for binding to different components of the extracellular matrix. Integrin expression changes depending on the type of cell, its developmental stage, or the pathological status. There is also an age-associated change in integrin expression which may, at least in part, be responsible for the high prevalence of age-associated disorders. The focus of this chapter is to discuss (1) general structure and function of integrins, (2) expression of integrins in the heart, (3) change in the expression of integrins in the heart during aging, (4) their role in regulation of the remodeling process of the heart, and (5) their therapeutic potential for treatment of heart failure.

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 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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. Hynes R. Integrins: a family of cell surface receptors. Cell. 1987;48:549–54.

    Article  CAS  PubMed  Google Scholar 

  2. Lowell C, Mayadas T. Overview: studying integrins in vivo. Methods Mol Biol. 2012;757:369–97.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Ross R, Borg T. Integrins and the myocardium. Circ Res. 2001;88:1112–21.

    Article  CAS  PubMed  Google Scholar 

  4. Hynes R. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.

    Article  CAS  PubMed  Google Scholar 

  5. Humphries M. Integrin structure. Biochem Soc Trans. 2000;28:311–39.

    Article  CAS  PubMed  Google Scholar 

  6. Campbell I, Humphries M. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol. 2011;3:a004994.

    Article  PubMed  Google Scholar 

  7. Meighan C, Schwarzbauer J. Temporal and spatial regulation of integrins during development. Curr Opin Cell Biol. 2008;20:520–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wu M, Fannin J, Rice K, Wang B, Blough E. Effect of aging on cellular mechanotransduction. Ageing Res Rev. 2011;10:1–15.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Zamir E, Geiger B. Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci. 2001;114:3583–90.

    CAS  PubMed  Google Scholar 

  10. Wozniak M, Modzelewska K, Kwong L, Keely P. Focal adhesion regulation of cell behavior. Biochim Biophys Acta. 2004;1692:103–19.

    Article  CAS  PubMed  Google Scholar 

  11. Galbraith C, Yamada K, Sheetz M. The relationship between force and focal complex development. J Cell Biol. 2002;159:695–705.

    Article  CAS  PubMed  Google Scholar 

  12. DePasquale J, Izzard C. Accumulation of talin in nodes at the edge of the lamellipodium and separate incorporation into adhesion plaques at focal contacts in fibroblasts. J Cell Biol. 1991;113:1351–9.

    Article  CAS  PubMed  Google Scholar 

  13. Laudanna C, Kim J, Constantin G, Butcher E. Rapid leukocyte integrin activation by chemokines. Immunol Rev. 2002;186:37–46.

    Article  CAS  PubMed  Google Scholar 

  14. Calderwood D. Talin controls integrin activation. Biochem Soc Trans. 2004;32:434–7.

    Article  CAS  PubMed  Google Scholar 

  15. Ross R. Molecular and mechanical synergy: cross-talk between integrins and growth factor receptors. Cardiovasc Res. 2004;63:381–90.

    Article  CAS  PubMed  Google Scholar 

  16. Munger J, Sheppard D. Cross talk among TGF-Beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol. 2011;3:a005017.

    Article  PubMed  Google Scholar 

  17. Nagai T, Laser M, Baicu C, Zile M, Cooper G, Kuppuswamy D. Beta3-integrin-mediated focal adhesion complex formation: adult cardiocytes embedded in three-dimensional polymer matrices. Am J Cardiol. 1999;83:38H–43.

    Article  CAS  PubMed  Google Scholar 

  18. van der Flier A, Kuikman I, Baudoin C, van der Neut R, Sonnenberg A. A novel beta 1 integrin isoform produced by alternative splicing: unique expression in cardiac and skeletal muscle. FEBS Lett. 1995;369:340–4.

    Article  PubMed  Google Scholar 

  19. Zhidkova N, Belkin A, Mayne R. Novel isoform of beta 1 integrin expressed in skeletal and cardiac muscle. Biochem Biophys Res Commun. 1995;214:279–85.

    Article  CAS  PubMed  Google Scholar 

  20. Ross R, Pham C, Shai S, Goldhaber J, Fenczik C, Glembotski C, Ginsberg M, Loftus J. Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes. Circ Res. 1998;82:1160–72.

    Article  CAS  PubMed  Google Scholar 

  21. MacKenna D, Summerour S, Villarreal F. Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res. 2000;46:257–63.

    Article  CAS  PubMed  Google Scholar 

  22. Harston R, Kuppuswamy D. Integrins are the necessary links to hypertrophic growth in cardiomyocytes. J Signal Transduct. 2011;2011:521742.

    PubMed Central  PubMed  Google Scholar 

  23. Katsumi A, Orr A, Tzima E, Schwartz M. Integrins in mechanotransduction. J Biol Chem. 2004;279:12001–4.

    Article  CAS  PubMed  Google Scholar 

  24. Edgley A, Krum H, Kelly D. Targeting fibrosis for the treatment of heart failure: a role for transforming growth factor-beta. Cardiovasc Ther. 2012;30:e30–40.

    Article  CAS  PubMed  Google Scholar 

  25. Dabiri B, Lee H, Parker K. A potential role for integrin signaling in mechanoelectrical feedback progress in biophysics and molecular biology. Prog Biophys Mol Biol. 2012;110(2–3):196–203.

    Article  CAS  PubMed  Google Scholar 

  26. Burgess M, McCrea J, Hedrick H. Age-associated changes in cardiac matrix and integrins. Mech Ageing Dev. 2001;122:1739–56.

    Article  CAS  PubMed  Google Scholar 

  27. Sottile J, Hocking D. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions. Mol Biol Cell. 2002;13:3546–59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Mamuya W, Chobanian A, Brecher P. Age-related changes in fibronectin expression in spontaneously hypertensive, Wistar-Kyoto, and Wistar rat hearts. Circ Res. 1992;71:1341–50.

    Article  CAS  PubMed  Google Scholar 

  29. Wilson CG, Stone JW, Fowlkes V, Morales MO, Murphy CJ, Baxter SC, Goldsmith EC. Age-dependent expression of collagen receptors and deformation of type I collagen substrates by rat cardiac fibroblasts. Microsc Microanal. 2011;17:555–62.

    Article  CAS  PubMed  Google Scholar 

  30. Communal C, Huq F, Lebeche D, Mestel C, Gwathmey J, Hajjar R. Decreased efficiency of adenovirus-mediated gene transfer in aging cardiomyocytes. Circulation. 2003;107:1170–5.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79:215–62.

    CAS  PubMed  Google Scholar 

  32. Shih H, Lee B, Lee R, Boyle A. The aging heart and post-infarction left ventricular remodeling. J Am Coll Cardiol. 2011;57:9–17.

    Article  PubMed  Google Scholar 

  33. Sun M, Opavsky M, Stewart D, Rabinovitch M, Dawood F, Wen W-H, Liu P. Temporal response and localization of integrins beta1 and beta3 in the heart after myocardial infarction: regulation by cytokines. Circulation. 2003;107:1046–52.

    Article  CAS  PubMed  Google Scholar 

  34. Nawata J, Ohno I, Isoyama S, Suzuki J, Miura S, Ikeda J, Shirato K. Differential expression of alpha 1, alpha 3 and alpha 5 integrin subunits in acute and chronic stages of myocardial infarction in rats. Cardiovasc Res. 1999;43:371–81.

    Article  CAS  PubMed  Google Scholar 

  35. Bujak M, Kweon H, Chatila K, Li N, Taffet G, Frangogiannis N. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol. 2008;51:1384–92.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Bujak M, Frangogiannis N. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74:184–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Burns J, Issekutz T, Yagita H, Issekutz A. The alpha 4 beta 1 (very late antigen (VLA)-4, CD49d/CD29) and alpha 5 beta 1 (VLA-5, CD49e/CD29) integrins mediate beta 2 (CD11/CD18) integrin-independent neutrophil recruitment to endotoxin-induced lung inflammation. J Immunol. 2001;166:4644–9.

    CAS  PubMed  Google Scholar 

  38. Pfister R, Acksteiner C, Baumgarth J, Burst V, Geissler H, Margulies K, Houser S, Bloch W, Flesch M. Loss of beta1D-integrin function in human ischemic cardiomyopathy. Basic Res Cardiol. 2007;102:257–64.

    Article  CAS  PubMed  Google Scholar 

  39. Shai S-Y, Harpf A, Babbitt C, Jordan M, Fishbein M, Chen J, Omura M, Leil T, Becker K, Jiang M, Smith D, Cherry S, Loftus J, Ross R. Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circ Res. 2002;90:458–64.

    Article  CAS  PubMed  Google Scholar 

  40. Krishnamurthy P, Subramanian V, Singh M, Singh K. Deficiency of beta1 integrins results in increased myocardial dysfunction after myocardial infarction. Heart (British Cardiac Society). 2006;92:1309–15.

    Article  CAS  Google Scholar 

  41. Calderwood D. Integrin activation. J Cell Sci. 2004;117:657–66.

    Article  CAS  PubMed  Google Scholar 

  42. Ding B, Price R, Goldsmith E, Borg T, Yan X, Douglas P, Weinberg E, Bartunek J, Thielen T, Didenko V, Lorell B. Left ventricular hypertrophy in ascending aortic stenosis mice: anoikis and the progression to early failure. Circulation. 2000;101:2854–62.

    Article  CAS  PubMed  Google Scholar 

  43. Hooper N, Karran E, Turner A. Membrane protein secretases. Biochem J. 1997;321(Pt 2):265–79.

    CAS  PubMed  Google Scholar 

  44. Manso A, Elsherif L, Kang S-M, Ross R. Integrins, membrane-type matrix metalloproteinases and ADAMs: potential implications for cardiac remodeling. Cardiovasc Res. 2006;69:574–84.

    Article  CAS  PubMed  Google Scholar 

  45. Eckhouse S, Spinale F. Changes in the myocardial interstitium and contribution to the progression of heart failure. Heart Fail Clin. 2012;8:7–20.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Li J, Du W, Jiang S, Tian H. Expression of ADAM-15 in rat myocardial infarction. Int J Exp Pathol. 2009;90:347–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Olivetti G, Melissari M, Capasso J, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–8.

    Article  CAS  PubMed  Google Scholar 

  48. Goldsmith E, Carver W, McFadden A, Goldsmith J, Price R, Sussman M, Lorell B, Cooper G, Borg T. Integrin shedding as a mechanism of cellular adaptation during cardiac growth. Am J Physiol Heart Circ Physiol. 2003;284:H2227–34.

    CAS  PubMed  Google Scholar 

  49. Menon B, Krishnamurthy P, Kaverina E, Johnson J, Ross R, Singh M, Singh K. Expression of the cytoplasmic domain of beta1 integrin induces apoptosis in adult rat ventricular myocytes (ARVM) via the involvement of caspase-8 and mitochondrial death pathway. Basic Res Cardiol. 2006;101:485–93.

    Article  CAS  PubMed  Google Scholar 

  50. van Empel V, Bertrand A, Hofstra L, Crijns H, Doevendans P, De Windt L. Myocyte apoptosis in heart failure. Cardiovasc Res. 2005;67:21–9.

    Article  PubMed  Google Scholar 

  51. Chen L, Knowlton AA. Mitochondrial dynamics in heart failure. Congest Heart Fail. 2011;17:257–61.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Sheydina A, Riordon DR, Boheler KR. Molecular mechanisms of cardiomyocyte aging. Clin Sci (Lond). 2011;121:315–29.

    Article  CAS  Google Scholar 

  53. Hasking G, Esler M, Jennings G, Burton D, Johns J, Korner P. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986;73:615–21.

    Article  CAS  PubMed  Google Scholar 

  54. Karlsberg R, Penkoske P, Cryer P, Corr P, Roberts R. Rapid activation of the sympathetic nervous system following coronary artery occlusion: relationship to infarct size, site, and haemodynamic impact. Cardiovasc Res. 1979;13:523–31.

    Article  CAS  PubMed  Google Scholar 

  55. Graham L, Smith P, Stoker J, Mackintosh A, Mary D. Time course of sympathetic neural hyperactivity after uncomplicated acute myocardial infarction. Circulation. 2002;106:793–7.

    Article  PubMed  Google Scholar 

  56. Margiocco M, Borgarelli M, Musch T, Hirai D, Hageman K, Fels R, Garcia A, Kenney M. Effects of combined aging and heart failure on visceral sympathetic nerve and cardiovascular responses to progressive hyperthermia in F344 rats. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1555–63.

    Article  CAS  PubMed  Google Scholar 

  57. Amin P, Singh M, Singh K. Beta-adrenergic receptor-stimulated cardiac myocyte apoptosis: role of beta1 integrins. J Sig Transduct. 2011;2011:179057.

    Google Scholar 

  58. Daaka Y, Luttrell L, Lefkowitz R. Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature. 1997;390:88–91.

    Article  CAS  PubMed  Google Scholar 

  59. Nikolaev V, Moshkov A, Lyon A, Miragoli M, Novak P, Paur H, Lohse M, Korchev Y, Harding S, Gorelik J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science (New York, NY). 2010;327:1653–7.

    Article  CAS  Google Scholar 

  60. Communal C, Singh M, Menon B, Xie Z, Colucci W, Singh K. Beta1 integrins expression in adult rat ventricular myocytes and its role in the regulation of beta-adrenergic receptor-stimulated apoptosis. J Cell Biochem. 2003;89:381–8.

    Article  CAS  PubMed  Google Scholar 

  61. Krishnamurthy P, Subramanian V, Singh M, Singh K. Beta1 integrins modulate beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. Hypertension. 2007;49:865–72.

    Article  CAS  PubMed  Google Scholar 

  62. Menon B, Singh M, Singh K. Matrix metalloproteinases mediate beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes. Am J Physiol Cell Physiol. 2005;289:C168–76.

    Article  CAS  PubMed  Google Scholar 

  63. Menon B, Singh M, Ross R, Johnson J, Singh K. Beta-adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of beta1 integrin signaling and mitochondrial pathway. Am J Physiol Cell Physiol. 2006;290:C254–61.

    Article  CAS  PubMed  Google Scholar 

  64. Boyle A, Shih H, Hwang J, Ye J, Lee B, Zhang Y, Kwon D, Jun K, Zheng D, Sievers R, Angeli F, Yeghiazarians Y, Lee R. Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. Exp Gerontol. 2011;46:549–59.

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Terracio L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R, Borg T. Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res. 1991;68:734–44.

    Article  CAS  PubMed  Google Scholar 

  67. Burgess M, Terracio L, Hirozane T, Borg T. Differential integrin expression by cardiac fibroblasts from hypertensive and exercise-trained rat hearts. Cardiovasc Pathol. 2002;11:78–87.

    Article  CAS  PubMed  Google Scholar 

  68. Willey C, Balasubramanian S, Rodriguez Rosas MC, Ross R, Kuppuswamy D. Focal complex formation in adult cardiomyocytes is accompanied by the activation of beta3 integrin and c-Src. J Mol Cell Cardiol. 2003;35:671–83.

    Article  CAS  PubMed  Google Scholar 

  69. Ren J, Avery J, Zhao H, Schneider J, Ross F, Muslin A. Beta3 integrin deficiency promotes cardiac hypertrophy and inflammation. J Mol Cell Cardiol. 2007;42:367–77.

    Article  CAS  PubMed  Google Scholar 

  70. Johnston RK, Balasubramanian S, Kasiganesan H, Baicu CF, Zile MR, Kuppuswamy D. Beta3 integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy. FASEB J. 2009;23:2759–71.

    Article  CAS  PubMed  Google Scholar 

  71. Konstam M, Kramer D, Patel A, Maron M, Udelson J. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4:98–108.

    Article  PubMed  Google Scholar 

  72. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S. Heart outcomes prevention evaluation I. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104:1615–21.

    Article  CAS  PubMed  Google Scholar 

  73. Kawano H, Cody R, Graf K, Goetze S, Kawano Y, Schnee J, Law R, Hsueh W. Angiotensin II enhances integrin and alpha-actinin expression in adult rat cardiac fibroblasts. Hypertension. 2000;35:273–9.

    Article  CAS  PubMed  Google Scholar 

  74. Brooks W, Conrad C. Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol. 2000;32:187–95.

    Article  CAS  PubMed  Google Scholar 

  75. Aluwihare P, Mu Z, Zhao Z, Yu D, Weinreb P, Horan G, Violette S, Munger J. Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgf-beta1 and Tgf-beta3 null mice. J Cell Sci. 2009;122:227–32.

    Article  CAS  PubMed  Google Scholar 

  76. Schmidt U, del Monte F, Miyamoto M, Matsui T, Gwathmey J, Rosenzweig A, Hajjar R. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation. 2000;101:790–6.

    Article  CAS  PubMed  Google Scholar 

  77. Sherif H, Saraste A, Nekolla S, Weidl E, Reder S, Tapfer A, Rudelius M, Higuchi T, Botnar R, Wester HJ, Schwaiger M. Molecular imaging of early alphav beta3 integrin expression predicts long-term left-ventricle remodeling after myocardial infarction in rats. J Nucl Med. 2012;53:318–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work is supported by the National Institutes of Health (Grant numbers HL-091405 and HL-092459 to KS) and a Merit Review award (number BX000640 to KS) from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Laura L. Daniel BS, William L. Joyner PhD & Mahipal Singh PhD

  2. Department of Biomedical Sciences, East Tennessee State University, 70582, Johnson City, TN, 37614, USA

    Krishna Singh PhD

Authors
  1. Laura L. Daniel BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William L. Joyner PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahipal Singh PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Krishna Singh PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krishna Singh PhD .

Editor information

Editors and Affiliations

  1. Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta and Hospitals, Edmonton, Alberta, Canada

    Bodh I. Jugdutt

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Daniel, L.L., Joyner, W.L., Singh, M., Singh, K. (2014). Integrins: Implications for Aging in Heart Failure Therapy. In: Jugdutt, B. (eds) Aging and Heart Failure. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0268-2_27

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0268-2_27

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-0267-5

  • Online ISBN: 978-1-4939-0268-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation