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Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

Publication ,  Journal Article
Freeman, K; Lerman, I; Kranias, EG; Bohlmeyer, T; Bristow, MR; Lefkowitz, RJ; Iaccarino, G; Koch, WJ; Leinwand, LA
Published in: J Clin Invest
April 2001

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

April 2001

Volume

107

Issue

8

Start / End Page

967 / 974

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Adrenergic, beta-2
  • Myosin Heavy Chains
  • Myocardium
  • Motor Activity
  • Mice, Transgenic
  • Mice
  • Male
  • Immunology
  • Heart Failure
 

Citation

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Freeman, K., Lerman, I., Kranias, E. G., Bohlmeyer, T., Bristow, M. R., Lefkowitz, R. J., … Leinwand, L. A. (2001). Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest, 107(8), 967–974. https://doi.org/10.1172/JCI12083
Freeman, K., I. Lerman, E. G. Kranias, T. Bohlmeyer, M. R. Bristow, R. J. Lefkowitz, G. Iaccarino, W. J. Koch, and L. A. Leinwand. “Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.J Clin Invest 107, no. 8 (April 2001): 967–74. https://doi.org/10.1172/JCI12083.
Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, et al. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest. 2001 Apr;107(8):967–74.
Freeman, K., et al. “Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.J Clin Invest, vol. 107, no. 8, Apr. 2001, pp. 967–74. Pubmed, doi:10.1172/JCI12083.
Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest. 2001 Apr;107(8):967–974.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

April 2001

Volume

107

Issue

8

Start / End Page

967 / 974

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Adrenergic, beta-2
  • Myosin Heavy Chains
  • Myocardium
  • Motor Activity
  • Mice, Transgenic
  • Mice
  • Male
  • Immunology
  • Heart Failure