Reduced betaARK1 activity in genetically targeted mice significantly increased myocardial contractile function and cellular responsiveness to isoproterenol compared with wild-type mice.
Does partial inhibition of betaARK1 activity improve myocardial contractile function in a mouse model?
Partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling and improves myocardial contractile function, suggesting betaARK1 as a potential therapeutic target in heart failure.
We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 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), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct 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 betaARK1(+/-) and betaARK1(+/-)betaARKct 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 betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.
Rockman et al. (Wed,) reported a other. Reduced betaARK1 activity (betaARK1(+/-) and betaARK1(+/-)betaARKct genotypes) vs. Wild-type mice was evaluated on Myocardial contractile function (percent and rate of cell shortening following isoproterenol stimulation). Reduced betaARK1 activity in genetically targeted mice significantly increased myocardial contractile function and cellular responsiveness to isoproterenol compared with wild-type mice.