CONTROL OF MYOCARDIAL CONTRACTILE FUNCTION BY THE LEVEL OF BETA-ADRENERGIC-RECEPTOR KINASE-1 IN GENE-TARGETED MICE

We studied the effect of alterations in the level of myocardial beta-a drenergic receptor kinase (beta ARK1) in two types of genetically alte red 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 overexpressi on of a beta ARK1 COOH-terminal inhibitor pep tide, beta ARK1(+/-)/bet a ARKct. In contrast to the embryonic lethal phenotype of the homozygo us 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 p erformed in mice and showed a stepwise increase in contractile functio n in the beta ARK1(+/-) and beta ARK1(+/-)/beta ARKct mice with the gr eatest level observed in the beta ARK1(+/-)/beta ARKct animals. Contra ctile parameters were measured in adult myocytes isolated from both gr oups of gene-targeted animals. A significantly greater increase in per cent cell shortening and rate of cell shortening following isoproteren ol stimulation was observed in the beta ARK1(+/-) and beta ARK1(+/-)/b eta ARKct myocytes compared with wild-type cells, indicating a progres sive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of beta ARK1 activi ty. This has important implications in disease states such as heart fa ilure (in which beta ARK1 activity is increased) and suggests that bet a ARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of beta ARK1 activity enhances beta-adrenergi c receptor signaling leading to improved functional catecholamine resp onsiveness.