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 beta-adrenergic receptor kinase (beta ARK1) in two types of genetically altered mice. The first group is heterozygous for beta ARK1 gene ablation, beta ARK1(+/-), and the second is not only heterozygous for beta AR1 gene ablation but is also transgenic for cardiac-specific overexpression of a beta ARK1 COOH-terminal inhibitor pep tide, beta ARK1(+/-)/beta ARKct. In contrast to the embryonic lethal phenotype of the homozygous beta 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), beta ARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the beta ARK1(+/-) and beta ARK1(+/-)/beta ARKct mice with the greatest level observed in the beta ARK1(+/-)/beta 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 beta ARK1(+/-) and beta ARK1(+/-)/beta 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 beta ARK1 activity. This has important implications in disease states such as heart failure (in which beta ARK1 activity is increased) and suggests that beta ARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of beta ARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.