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Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

Publication ,  Journal Article
Kohout, TA; Takaoka, H; McDonald, PH; Perry, SJ; Mao, L; Lefkowitz, RJ; Rockman, HA
Published in: Circulation
November 13, 2001

BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. METHODS AND RESULTS: To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity. CONCLUSIONS: Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 13, 2001

Volume

104

Issue

20

Start / End Page

2485 / 2491

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Transcription, Genetic
  • Sulfonamides
  • Stimulation, Chemical
  • Signal Transduction
  • Receptors, Adrenergic, beta-3
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
 

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Kohout, T. A., Takaoka, H., McDonald, P. H., Perry, S. J., Mao, L., Lefkowitz, R. J., & Rockman, H. A. (2001). Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation, 104(20), 2485–2491. https://doi.org/10.1161/hc4501.098933
Kohout, T. A., H. Takaoka, P. H. McDonald, S. J. Perry, L. Mao, R. J. Lefkowitz, and H. A. Rockman. “Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.Circulation 104, no. 20 (November 13, 2001): 2485–91. https://doi.org/10.1161/hc4501.098933.
Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, et al. Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation. 2001 Nov 13;104(20):2485–91.
Kohout, T. A., et al. “Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.Circulation, vol. 104, no. 20, Nov. 2001, pp. 2485–91. Pubmed, doi:10.1161/hc4501.098933.
Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, Rockman HA. Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation. 2001 Nov 13;104(20):2485–2491.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 13, 2001

Volume

104

Issue

20

Start / End Page

2485 / 2491

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Transcription, Genetic
  • Sulfonamides
  • Stimulation, Chemical
  • Signal Transduction
  • Receptors, Adrenergic, beta-3
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice