(Circulation. 2000;102:2751.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Physiological Induction of a ß-Adrenergic Receptor Kinase Inhibitor Transgene Preserves ß-Adrenergic Responsiveness in Pressure-Overload Cardiac Hypertrophy
From the Departments of Surgery (B.S.M., K.S., W.J.K.) and Medicine (L.M., H.A.R.), Duke University Medical Center, Durham, NC. Dr Manning is currently with Obesity Molecular Sciences, CVMD Discovery, Pfizer Global Research and Development, Groton Laboratories, Groton, Conn.
Correspondence to Walter J. Koch, PhD, Duke University Medical Center, Box 2606, Room 472 MSRB, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
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.
Key Words: receptors, adrenergic, beta • hypertrophy • genetics
This article has been cited by other articles:
 |
|
 |
|
  S. J. Matkovich, A. Diwan, J. L. Klanke, D. J. Hammer, Y. Marreez, A. M. Odley, E. W. Brunskill, W. J. Koch, R. J. Schwartz, and G. W. Dorn II Cardiac-Specific Ablation of G-Protein Receptor Kinase 2 Redefines Its Roles in Heart Development and {beta}-Adrenergic Signaling Circ. Res., October 27, 2006; 99(9): 996 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Nordlie, L. E. Wold, B. Z. Simkhovich, C. Sesti, and R. A. Kloner Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion-Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 17 - 30. [Abstract] [PDF]
|
|
|
|
 |
|
 C. R. Bridges, K. Gopal, D. E. Holt, C. Yarnall, S. Cole, R. B. Anderson, X. Yin, A. Nelson, B. W. Kozyak, Z. Wang, et al. Efficient myocyte gene delivery with complete cardiac surgical isolation in situ J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1364 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Holmes Candidate mechanical stimuli for hypertrophy during volume overload J Appl Physiol, October 1, 2004; 97(4): 1453 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A Movsesian Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy Cardiovasc Res, June 1, 2004; 62(3): 450 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Williams, J. A. Hata, J. Schroder, E. Rampersaud, J. Petrofski, A. Jakoi, C. A. Milano, and W. J. Koch Targeted {beta}-Adrenergic Receptor Kinase ({beta}ARK1) Inhibition by Gene Transfer in Failing Human Hearts Circulation, April 6, 2004; 109(13): 1590 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Torrado, E. Lopez, A. Centeno, A. Castro-Beiras, and A. T. Mikhailov Left-right asymmetric ventricular expression of CARP in the piglet heart: regional response to experimental heart failure Eur J Heart Fail, March 1, 2004; 6(2): 161 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. G. Dobson, J. Fray, J. L. Leonard, and R. E. Pratt Molecular mechanisms of reduced {beta}-adrenergic signaling in the aged heart as revealed by genomic profiling Physiol Genomics, October 17, 2003; 15(2): 142 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hata and W. J. Koch Phosphorylation of G Protein-Coupled Receptors: GPCR Kinases in Heart Disease Mol. Interv., August 1, 2003; 3(5): 264 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. de Waard, T. A.E. van Achterberg, N. J. Beauchamp, H. Pannekoek, and C. J.M. de Vries Cardiac Ankyrin Repeat Protein (CARP) Expression in Human and Murine Atherosclerotic Lesions: Activin Induces Carp in Smooth Muscle Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 64 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kim, A. D. Eckhart, S. Eguchi, and W. J. Koch beta -Adrenergic Receptor-mediated DNA Synthesis in Cardiac Fibroblasts Is Dependent on Transactivation of the Epidermal Growth Factor Receptor and Subsequent Activation of Extracellular Signal-regulated Kinases J. Biol. Chem., August 23, 2002; 277(35): 32116 - 32123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Steinberg G protein-coupled receptor kinases: gotta real kure for heart failure? J. Am. Coll. Cardiol., August 1, 2001; 38(2): 541 - 545. [Full Text] [PDF]
|
|
|
|
|
|
X.-J. Du Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice Cardiovasc Res, June 1, 2001; 50(3): 443 - 453. [Full Text] [PDF]
|
|
|
|
|
|
C. L. Antos, N. Frey, S. O. Marx, S. Reiken, M. Gaburjakova, J. A. Richardson, A. R. Marks, and E. N. Olson Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A Circ. Res., November 23, 2001; 89(11): 997 - 1004. [Abstract] [Full Text] [PDF]
|
|