Reciprocal in vivo regulation of myocardial g protein-coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade
Reciprocal in vivo regulation of myocardial g protein-coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade
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DOI：
10.1161/01.cir.98.17.1783
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发表时间：
1998-10-27
期刊：
影响因子：
37.8
通讯作者：
Koch, WJ
中科院分区：
文献类型：
--
作者：
Iaccarino, G;Tomhave, ED;Koch, WJ
心肌β -肾上腺素能受体（β - AR）信号受损，包括脱敏和功能解偶联，是充血性心力衰竭的一个特征。这种损伤的机制可能与心肌β -肾上腺素能受体激酶（β ARK1）活性增强有关，因为这种β ar脱敏G蛋白偶联受体激酶（GRK）的水平在心力衰竭时升高。一种假说认为，与心力衰竭相关的交感神经系统活动增加可能是β - AR信号改变（包括脱敏）的初始刺激因素。我们用激活或拮抗β - AR的药物长期治疗小鼠，研究β - AR激活与心肌β - ARK1水平之间的动态关系。方法和结果：长期在体内刺激β - AR可导致心脏β - AR信号通路受损，β - ARK1的表达水平（mRNA和蛋白）和活性升高，但GRK5（心肌中大量表达的第二种GRK）的表达水平和活性未升高。长期β受体阻滞剂治疗，包括卡维地洛的使用，以特异性和剂量依赖性的方式改善心肌β - AR信号传导并降低β - ARK1水平。在体外培养的细胞中获得了相同的结果，表明GRK表达的调节与β - AR信号传导直接相关。结论：本报告首次证明β - AR刺激可显著增加β - ARK1的表达，而β -阻断则会降低表达。这种β ARK1的相互调节记录了配体诱导β AR调节的新机制，并为β受体阻滞剂（如卡维地洛）治疗心力衰竭的有效性提供了重要的潜在机制。
Background-Impaired myocardial beta-adrenergic receptor (beta AR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (beta ARK1) activity because levels of this beta AR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for beta AR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize beta ARs to study the dynamic relationship between beta AR activation and myocardial levels of beta ARK1.Methods and Results-Long-term in vivo stimulation of beta ARs results in the impairment of cardiac beta AR signaling and increases the level of expression (mRNA and protein) and activity of beta ARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial beta AR signaling and reduces beta ARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to beta AR signaling.Conclusions-This report demonstrates, for the first time, that beta AR stimulation can significantly increase the expression of beta ARK1, whereas beta-blockade decreases expression. This reciprocal regulation of beta ARK1 documents a novel mechanism of ligand-induced beta AR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.