Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure

Abstract

Catecholamines stimulate cardiac contractility through β1-adrenergic receptors (β1-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased β-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and Gαs expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to β-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to β-receptor blockade.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Functional consequences of polymorphic β1-AR expression in transgenic mouse hearts.
Figure 2: Phenotypic switching of Arg389 and Gly389 β1-AR signaling in mouse and human ventricles.
Figure 3: Cardiac gene expression profiles from polymorphic β1-AR transgenic mice.
Figure 4: Allele-specific features of Arg389 and Gly389 β1-AR in transgenic mice and human heart failure.
Figure 5: Altered expression of calcium-cycling and β-AR signaling proteins in 6-month-old Arg389 hearts.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Givertz, M.M. Underlying causes and survival in patients with heart failure. N. Engl. J. Med. 342, 1120–1122 (2000).

    Article  CAS  Google Scholar 

  2. van Campen, L.C., Visser, F.C. & Visser, C.A. Ejection fraction improvement by beta-blocker treatment in patients with heart failure: an analysis of studies published in the literature. J. Cardiovasc. Pharmacol. 32 (suppl. 1), S31–S35 (1998).

    CAS  PubMed  Google Scholar 

  3. Franz, W.-M., Müller, O.J. & Katus, H.A. Cardiomyopathies: from genetics to the prospect of treatment. Lancet 358, 1627–1637 (2001).

    Article  CAS  Google Scholar 

  4. Engelhardt, S., Hein, L., Wiesmann, F. & Lohse, M.J. Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc. Natl. Acad. Sci. USA 96, 7059–7064 (1999).

    Article  CAS  Google Scholar 

  5. Liggett, S.B. β-adrenergic receptors in the failing heart: the good, the bad, and the unknown. J. Clin. Invest. 107, 947–948 (2001).

    Article  CAS  Google Scholar 

  6. Mason, D.A., Moore, J.D., Green, S.A. & Liggett, S.B. A gain-of-function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor. J. Biol. Chem. 274, 12670–12674 (1999).

    Article  CAS  Google Scholar 

  7. Moore, J.D., Mason, D.A., Green, S.A., Hsu, J. & Liggett, S.B. Racial differences in the frequencies of cardiac β1-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum. Mutat. 14, 271–271 (1999).

    Article  CAS  Google Scholar 

  8. Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000).

    Article  CAS  Google Scholar 

  9. Small, K.M., Wagoner, L.E., Levin, A.M., Kardia, S.L.R. & Liggett, S.B. Synergistic polymorphisms of β1- and α2C-adrenergic receptors and the risk of congestive heart failure. N. Engl. J. Med. 347, 1135–1142 (2002).

    Article  CAS  Google Scholar 

  10. Wagoner, L.E. et al. Polymorphisms of the β1-adrenergic receptor predict exercise capacity in heart failure. Am. Heart J. 144, 840–846 (2002).

    Article  CAS  Google Scholar 

  11. Bengtsson, K. et al. Polymorphism in the β1-adrenergic receptor gene and hypertension. Circulation 104, 187–190 (2001).

    Article  CAS  Google Scholar 

  12. D'Angelo, D.D. et al. Transgenic Gαq overexpression induces cardiac contractile failure in mice. Proc. Natl. Acad. Sci. USA 94, 8121–8126 (1997).

    Article  CAS  Google Scholar 

  13. Liggett, S.B. et al. Early and delayed consequences of β2-adrenergic receptor overexpression in mouse hearts. Circulation 101, 1707–1714 (2000).

    Article  CAS  Google Scholar 

  14. Bristow, M.R. et al. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N. Engl. J. Med. 307, 205–211 (1982).

    Article  CAS  Google Scholar 

  15. Bristow, M.R., Hershberger, R.E., Port, J.D., Minobe, W. & Rasmussen, R. β1- and β2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol. Pharmacol. 35, 295–303 (1988).

    Google Scholar 

  16. Dunigan, C.D., Hoang, Q., Curran, P.K. & Fishman, P.H. Complexity of agonist- and cyclic AMP-mediated downregulation of the human β1-adrenergic receptor: role of internalization, degradation, and mRNA destabilization. Biochem. 41, 8019–8030 (2002).

    Article  CAS  Google Scholar 

  17. Dorn, G.W.I., Tepe, N.M., Wu, G., Yatani, A. & Liggett, S.B. Mechanisms of impaired β-adrenergic receptor signaling in Gαq-mediated cardiac hypertrophy and ventricular dysfunction. Mol. Pharmacol. 57, 278–287 (2000).

    CAS  PubMed  Google Scholar 

  18. Bohm, M. et al. Desensitization of adenylate cyclase and increase of Gi alpha in cardiac hypertrophy due to acquired hypertension. Hypertension 20, 103–112 (1992).

    Article  CAS  Google Scholar 

  19. Ungerer, M., Bohm, M., Elce, J.S., Erdmann, E. & Lohse, M.J. Altered expression of beta-adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart. Circulation 87, 454–463 (1993).

    Article  CAS  Google Scholar 

  20. Bohm, M. et al. Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82, 1249–1265 (1990).

    Article  CAS  Google Scholar 

  21. Eschenhagen, T. et al. Increased messenger RNA level of the inhibitory G protein α subunit Giα-2 in human end-stage heart failure. Circ. Res. 70, 688–696 (1992).

    Article  CAS  Google Scholar 

  22. Packer, M. et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 106, 2164–2166 (2002).

    Article  Google Scholar 

  23. Bristow, M.R. et al. β1- and β2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β1-receptor downregulation in heart failure. Circ. Res. 59, 297–309 (1986).

    Article  CAS  Google Scholar 

  24. Rathz, D.A., Gregory, K.N., Fang, Y., Brown, K.M. & Liggett, S.B. Hierarchy of polymorphic variation and desensitization permutations relative to β1- and β2-adrenergic receptor signaling. J. Biol. Chem. 278, 10784–10789 (2003).

    Article  CAS  Google Scholar 

  25. Yussman, M.G. et al. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat. Med. 8, 725–730 (2002).

    Article  CAS  Google Scholar 

  26. Serikov, V.B., Petrashevskaya, N.N., Canning, A.M. & Schwartz, A. Reduction of [Ca2+]i restores uncoupled beta-adrenergic signaling in isolated perfused transgenic mouse hearts. Circ. Res. 88, 9–11 (2001).

    Article  CAS  Google Scholar 

  27. Tepe, N.M. et al. Altering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: enhanced basal catalytic activity and function without increased cardiomyocyte β-adrenergic signalling. Biochemistry 38, 16706–16713 (1999).

    Article  CAS  Google Scholar 

  28. Small, K.M., Rathz, D.A. & Liggett, S.B. Identification of adrenergic receptor polymorphisms. Methods Enzymol. 343, 459–475 (2002).

    Article  Google Scholar 

  29. Wagoner, L.E. et al. Polymorphisms of the β2-adrenergic receptor determine exercise capacity in patients with heart failure. Circ. Res. 86, 834–840 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants HL22619, HL52318 and ES06096.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen B Liggett.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perez, J., Rathz, D., Petrashevskaya, N. et al. β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9, 1300–1305 (2003). https://doi.org/10.1038/nm930

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm930

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing