Skip to main content
SpringerLink
Log in

Genetic and phenotypic targeting of β-adrenergic signaling in heart failure

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Heart failure is a leading cause of hospitalization worldwide. No major significant improvements in prognosis have been achieved for heart failure over the last several decades despite advances in disease management. Heart failure itself represents a final common endpoint for several disease entities, including hypertension and coronary artery disease. On a molecular level, certain biochemical features remain common to failing myocardium. Among these are alterations in the β-adrenergic receptor (β-AR) signaling cascade. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies for management of heart failure via genetic manipulation of β-AR signaling including the targeted inhibition of the β-AR kinase (βARK1 or GRK2). In this review, we will discuss the β-AR signaling changes that accompany heart failure as well as corresponding therapeutic strategies. We will then review the evidence from transgenic mouse work supporting the use of β-AR manipulation in the failing heart and more recent in vivo applications of gene therapy directed at reversing or preventing heart failure. (Mol Cell Biochem 263: 5–9, 2004)

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

Similar content being viewed by others

References

  1. Leimbach WN, Wallin G, Victor RG, Aylward PE, Sundlof G, Mark AL: Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 93: 720–729, 1986

    Google Scholar 

  2. Rockman HA, Koch WJ, Lefkowitz RJ: Seven membrane spanning re-ceptors and heart function. Nature 415: 206–212, 2002

    Google Scholar 

  3. Brodde OE:-adrenoreceptors in cardiac disease. Pharm Ther 60: 405–430, 1993

    Google Scholar 

  4. Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ:-adrenergic receptor kinase: Primary structure delineates a multigene family. Science 246: 235–240, 1989

    Google Scholar 

  5. Inglese J, Freedman NJ, Koch WJ, Lefkowitz RJ: Structure and mech-anism of the G protein-coupled receptor kinases. J Biol Chem 268: 23735–23738, 1993

    Google Scholar 

  6. Eckhart AD, Duncan SJ, Penn RB, Benovic JL, Lefkowitz RJ, Koch WJ: Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ Res 86: 43–50, 2000

    Google Scholar 

  7. Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ:-arrestin: A protein that regulates-adrenergic receptor function. Science 248: 1547–1550, 1990

    Google Scholar 

  8. Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ: Role of subunits of G proteins in targeting the-adrenergic receptor kinase to membrane-bound receptors. Science 257: 1264–1267, 1992

    Google Scholar 

  9. Koch WJ, Inglese J, Stone WC, Lefkowitz RJ: The binding site for the βα subunits of heterotrimetic G proteins on the-adrenergic receptor kinase. J Biol Chem 268: 8256–8260, 1993

    Google Scholar 

  10. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ: Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a ARK inhibitor. Science 268: 1350–1353, 1995

    Google Scholar 

  11. Koch WJ, Hawes BE, Allen LF, Lefkowitz RJ: Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G activation of p21 ras. Proc Natl Acad Sci USA 91: 12706–12710, 1994

    Google Scholar 

  12. Koch WJ, Hawes BE, Inglese J, Luttrell LM, Lefkowitz RJ: Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates Gβα-mediated signaling. J Biol Chem 269: 6193–6197, 1994

    Google Scholar 

  13. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB: Decreased cate-cholamine sensitivity and â-adrenergic-receptor density in failing hu-man hearts. N Engl J Med 307: 205–211, 1982

    Google Scholar 

  14. Packer M:The development of positive inotropic agents for chronic heart failure: How have we gone astray? J Am Coll Cardiol 22: 119A–126A, 1993

  15. Engelhardt S, Hein L, Wiesmann F, Lohse MJ: Progressive hypertrophy and heart failure in â-1 adrenergic receptor transgenic mice. Proc Natl Acad Sci USA 96: 7059–7064, 1999

    Google Scholar 

  16. Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ: Enhanced myocardial func-tion in transgenic mice overexpressing the â 2-adrenergic receptor. Science 264: 582–586, 1994

    Google Scholar 

  17. Communal C, Singh K, Sawyer DB, Colucci WS: Opposing effects of â 1-and â 2-adrenergic receptors on cardiac myocyte apoptosis: Role of a pertussis toxin-sensitive G protein. Circulation 100: 2210–2212, 1999

    Google Scholar 

  18. Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ: Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expres-sion by â-adrenergic receptor stimulation and blockade. Circulation 98: 1783–1789, 1998

    Google Scholar 

  19. Arber S, Hunter JJ, Ross J Jr, Hongo M, Sansig G, Borg J, Perriad JC, Chien KR, Caroni P: MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88: 393–403, 1997

    Google Scholar 

  20. Rockman HA, Chien KR, Choi D-J, Iaccarino G, Hunter JJ, Ross Jr, J, Lefkowitz RJ, Koch WJ: Expression of a â-adrenergic receptor kinase 1.9 inhibitor prevents the development of heart failure in gene targeted mice. Proc Natl Acad Sci USA 95: 7000–7005, 1998

    Google Scholar 

  21. Dorn GW, Tepe NM, Lorenz JN, Davis MG, Koch WJ, Liggett SB: Low-and high-transgenic expression of â 2-adrenergic receptors differentially affects cardiac hypertrophy and function in G q overexpressing mice. Proc Natl Acad Sci USA 96: 6400–6405, 1999

    Google Scholar 

  22. Freeman K, Olsson MC, Iaccarino G, Bristow MR, Lefkowitz RJ, Kranias EL, Koch WJ, Leinwand LA: Manipulation of cardiac adrenergic signaling and calcium cycling have markedly different effects on the progression of cardiomyopathy. J Clin Invest 107: 967–974, 2001

    Google Scholar 

  23. Akhter SA, Skaer CA, Kypson AP, McDonald PH, Peppel KC, Glower DD, Lefkowitz RJ, Koch WJ: Restoration of-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. Proc Natl Acad Sci USA 94: 12100–12105, 1997

    Google Scholar 

  24. Drazner MH, Peppel KC, Dyer S, Grant AO, Koch WJ, Lefkowitz RJ: Potentiation of â-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes. J Clin Invest 99: 288–296, 1997

    Google Scholar 

  25. Maurice JP, Hata JA, Shah AS, White DC, McDonald PH, Dolber PC, Wilson KH, Lefkowitz RJ, Glower DD, Koch WJ: Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary â 2-adrenergic receptor gene delivery. J Clin Invest 104: 21–29, 1999

    Google Scholar 

  26. White DC, Hata JA, Shah AS, Glower DD, Lefkowitz RJ, Koch WJ: Preservation of myocardial â-adrenergic receptor delays the develop-ment of heart failure following myocardial infarction. Proc Natl Acad Sci USA 97: 5428–5433, 2000

    Google Scholar 

  27. Shah AS, Lilly RE, Kypson AP, Tai O, Hata JA, Pippen A, Silvestry SC, Lefkowitz RJ, Glower DD, Koch WJ: Intracoronary adenovirus-mediated delivery and overexpression of the â 2-adrenergic receptor in the heart: Prospects for molecular ventricular assistance. Circulation 101: 408–414, 2000

    Google Scholar 

  28. Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ: In vivo ventricular gene delivery of a â-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103: 1311–1316, 2001

    Google Scholar 

  29. Maurice JP, Shah AS, Kypson AP, Hata JA, White DC, Glower DD, Koch WJ: Molecular â-adrenergic signaling abnormalities in failing rabbit hearts after infarction. Am J Physiol 276: H1853–H1860, 1999

    Google Scholar 

  30. Teichler Zallen D: US gene therapy in crisis. Trends Genet 16: 272–275, 2000

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Walter J. Koch

Authors
  1. Walter J. Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koch, W.J. Genetic and phenotypic targeting of β-adrenergic signaling in heart failure. Mol Cell Biochem 263, 5–9 (2004). https://doi.org/10.1023/B:MCBI.0000041843.64809.48

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:MCBI.0000041843.64809.48

Search

Navigation