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Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy.

Publication ,  Journal Article
Manning, BS; Shotwell, K; Mao, L; Rockman, HA; Koch, WJ
Published in: Circulation
November 28, 2000

BACKGROUND: Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the ss-adrenergic receptor kinase (ssARKct) have increased in vivo cardiac function and enhanced ss-adrenergic receptor (ssAR) responsiveness. METHODS AND RESULTS: In the present study, we created transgenic mice with myocardium-targeted ssARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-ssARKct transgenic mice have normal in vivo cardiac contractility and ssAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-ssARKct hearts had elevations in left ventricular mass similar to those in NLCs; however, TAC did induce demonstrable ssARKct expression in the transgenic hearts. TAC in NLC mice resulted in an upregulation of myocardial ssARK1 and a loss of ssAR-mediated inotropic reserve. Importantly, although ssARK1 was increased in the hypertrophic CARP-ssARKct mice, the in vivo loss of ssAR responsiveness was not seen after induced ssARKct expression. CONCLUSIONS: These results demonstrate that acute ssARK1 inhibition can restore lost myocardial ssAR responsiveness and inotropic reserve in vivo. Furthermore, these mice demonstrate the novel utility of the CARP promoter as an inducible element responsive to pathophysiological conditions in the adult heart.

Duke Scholars

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 28, 2000

Volume

102

Issue

22

Start / End Page

2751 / 2757

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transgenes
  • Receptors, Adrenergic, beta
  • RNA, Messenger
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Male
  • Hemodynamics
 

Citation

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Manning, B. S., Shotwell, K., Mao, L., Rockman, H. A., & Koch, W. J. (2000). Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy. Circulation, 102(22), 2751–2757. https://doi.org/10.1161/01.cir.102.22.2751
Manning, B. S., K. Shotwell, L. Mao, H. A. Rockman, and W. J. Koch. “Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy.Circulation 102, no. 22 (November 28, 2000): 2751–57. https://doi.org/10.1161/01.cir.102.22.2751.
Manning, B. S., et al. “Physiological induction of a beta-adrenergic receptor kinase inhibitor transgene preserves ss-adrenergic responsiveness in pressure-overload cardiac hypertrophy.Circulation, vol. 102, no. 22, Nov. 2000, pp. 2751–57. Pubmed, doi:10.1161/01.cir.102.22.2751.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 28, 2000

Volume

102

Issue

22

Start / End Page

2751 / 2757

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Transgenes
  • Receptors, Adrenergic, beta
  • RNA, Messenger
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Male
  • Hemodynamics