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

We studied the effect of alterations in the level of myocardial β-adrenergic receptor kinase (βARK1) in two types of genetically altered mice. The first group is heterozygous for βARK1 gene ablation, βARK1(+/−), and the second is not only heterozygous for βARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a βARK1 COOH-terminal inhibitor peptide, βARK1(+/−)/βARKct. In contrast to the embryonic lethal phenotype of the homozygous βARK1 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), βARK1(+/−) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the βARK1(+/−) and βARK1(+/−)/βARKct mice with the greatest level observed in the βARK1(+/−)/βARKct 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 βARK1(+/−) and βARK1(+/−)/βARKct 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 βARK1 activity. This has important implications in disease states such as heart failure (in which βARK1 activity is increased) and suggests that βARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of βARK1 activity enhances β-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.