Rockman H A, Choi D J, Akhter S A, Jaber M, Giros B, Lefkowitz R J, Caron M G, Koch W J
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Biol Chem. 1998 Jul 17;273(29):18180-4. doi: 10.1074/jbc.273.29.18180.
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.
我们研究了两种基因改造小鼠中心肌β-肾上腺素能受体激酶（βARK1）水平改变的影响。第一组是βARK1基因敲除杂合子，即βARK1(+/-)，第二组不仅是βARK1基因敲除杂合子，还转基因实现了心脏特异性过表达βARK1羧基末端抑制肽，即βARK1(+/-)βARKct。与纯合βARK1基因敲除小鼠的胚胎致死表型（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）不同，βARK1(+/-)小鼠正常发育。对小鼠进行了心脏导管插入术，结果显示βARK1(+/-)和βARK1(+/-)βARKct小鼠的收缩功能呈逐步增加，在βARK1(+/-)βARKct动物中观察到的水平最高。在从两组基因靶向动物分离的成年心肌细胞中测量了收缩参数。与野生型细胞相比，在βARK1(+/-)和βARK1(+/-)βARKct心肌细胞中，异丙肾上腺素刺激后细胞缩短百分比和细胞缩短速率的增加显著更大，表明内在收缩性逐渐增加。这些数据表明收缩功能可由βARK1活性水平调节。这在诸如心力衰竭（其中βARK1活性增加）等疾病状态中具有重要意义，并表明在这种情况下βARK1应被视为治疗靶点。即使对βARK1活性进行部分抑制也会增强β-肾上腺素能受体信号传导，从而改善功能性儿茶酚胺反应性。
