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J Biol Chem, Vol. 273, Issue 29, 18180-18184, July 17, 1998

Control of Myocardial Contractile Function by the Level of -Adrenergic Receptor Kinase 1 in Gene-targeted Mice

Howard A. Rockman, Dong-Ju Choi, Shahab A. Akhter^§, Mohamed Jaber^¶, Bruno Giros^¶, Robert J. Lefkowitz^§§, Marc G. Caron^¶§§, and Walter J. Koch^§

From the  Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 and Departments of ^§ Surgery, ^¶ Cell Biology, and  Medicine, ^§§ Howard Hughes Medical Institute, Duke University, Durham, North Carolina 27710

We studied the effect of alterations in the level of myocardial -adrenergic receptor kinase (ARK1) in two types of genetically altered mice. The first group is heterozygous for ARK1 gene ablation, ARK1(+/), and the second is not only heterozygous for ARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a ARK1 COOH-terminal inhibitor peptide, ARK1(+/)/ARKct. In contrast to the embryonic lethal phenotype of the homozygous ARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), ARK1(+/) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the ARK1(+/) and ARK1(+/)/ARKct mice with the greatest level observed in the ARK1(+/)/ARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the ARK1(+/) and ARK1(+/)/ARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of ARK1 activity. This has important implications in disease states such as heart failure (in which ARK1 activity is increased) and suggests that ARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of ARK1 activity enhances -adrenergic receptor signaling leading to improved functional catecholamine responsiveness.

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