In vivo inhibition of elevated myocardial β-adrenergic receptor kinase activity in hybrid transgenic mice restores normal β-adrenergic signaling and function

被引:76
作者
Akhter, SA
Eckhart, AD
Rockman, HA
Shotwell, K
Lefkowitz, RJ
Koch, WJ
机构
[1] Duke Univ, Med Ctr, Lab Mol Cardiovasc Biol, Dept Surg, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Med & Biochem, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
[4] Univ N Carolina, Dept Med Cardiol, Chapel Hill, NC USA
关键词
receptors; adrenergic; beta; G proteins; protein kinases; desensitization; heart failure; mice; transgenic; myocardium;
D O I
10.1161/01.CIR.100.6.648
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-The clinical syndrome of heart failure (KF) is characterized by an impaired cardiac beta-adrenergic receptor (PAR) system, which is critical in the regulation of myocardial function. Expression of the beta AR kinase (beta ARK1), which phosphorylates and uncouples beta ARs, is elevated in human EFF; this likely contributes to the abnormal PAR responsiveness that occurs with beta-agonist administration. We previously showed that transgenic mice with increased myocardial beta ARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous beta ARK1 activity in the heart led to enhanced myocardial function. Methods and Results-We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both beta ARK1 and an inhibitor of beta ARK1 activity to study the feasibility and functional consequences of the inhibition of elevated beta ARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of beta ARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial beta ARK1 levels remained elevated due to transgene expression, in vitro beta ARK1 activity returned to control levels and the percentage of beta ARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to beta AR stimulation was restored to normal in the hybrid double-transgenic mice. Conclusions-Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial beta ARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vive by a peptide that can, prevent agonist-stimulated desensitization of cardiac beta ARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.
引用
收藏
页码:648 / 653
页数:8
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