ALTERED EXPRESSION OF BETA-ADRENERGIC-RECEPTOR KINASE AND BETA-1-ADRENERGIC RECEPTORS IN THE FAILING HUMAN HEART
ALTERED EXPRESSION OF BETA-ADRENERGIC-RECEPTOR KINASE AND BETA-1-ADRENERGIC RECEPTORS IN THE FAILING HUMAN HEART
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DOI：
10.1161/01.cir.87.2.454
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发表时间：
1993-02-01
期刊：
影响因子：
37.8
通讯作者：
LOHSE, MJ
中科院分区：
文献类型：
--
作者：
UNGERER, M;BOHM, M;LOHSE, MJ
背景在慢性心力衰竭中，β-肾上腺素能受体激动剂的正性肌力作用大大降低，部分原因是心脏β-肾上腺素能受体的两种改变：功能丧失（受体解偶联）和数量减少（下调）。体外研究表明，导致β-肾上腺素能受体解偶联的主要机制涉及通过特异性β-肾上腺素能受体激酶（betaARK）使受体磷酸化。因此，我们研究了扩张型心肌病或缺血性心肌病患者左心室和非衰竭对照心室样本中β ARK和β肾上腺素能受体的表达。与对照心脏相比，衰竭心脏对β受体刺激的收缩反应降低，而对毛喉素和钙的收缩反应保持不变。通过定量聚合酶链反应测定β ARK、β 1-和β 2-受体以及甘油醛磷酸脱氢酶和β-肌动蛋白的信使RNA（mRNA）水平。此外，进行β ARK酶活性测定，并通过放射性配体结合测定β 1和β 2受体水平。在两种形式的心力衰竭中，betaARK mRNA水平几乎增加了三倍，并且betaARK活性增强。在两个失败组中，β 1受体mRNA水平和β 1受体数量均下降约50%，而β 2受体的这些水平没有改变。扩张型心肌病和缺血型心肌病的上述参数均无差异。除了在衰竭心脏中发现的其他改变外，对β受体激动剂的反应减弱似乎涉及β ARK表达增强和β 1受体表达减少的综合效应。
Background. In chronic heart failure, the positive inotropic effects of beta-adrenergic receptor agonists are greatly reduced, in part as a result of two alterations of the cardiac beta-adrenergic receptors: loss of their function (receptor uncoupling) and reduction of their number (downregulation). In vitro studies have shown that a major mechanism leading to beta-adrenergic receptor uncoupling involves phosphorylation of the receptors by the specific beta-adrenergic receptor kinase (betaARK).Methods and Results. We have therefore investigated expression of betaARK and beta-adrenergic receptors in samples from the left ventricles of patients with dilated cardiomyopathy or ischemic cardiomyopathy and from nonfailing control ventricles. Contractile responses to beta-receptor stimulation were decreased in the failing hearts compared with control hearts, whereas those to forskolin and calcium remained unchanged. The messenger RNA (mRNA) levels of betaARK, beta1- and beta2-receptors, and of glyceraldehyde phosphate dehydrogenase and beta-actin as controls were measured by quantitative polymerase chain reactions. In addition, betaARK enzyme activity assays were performed, and the levels of beta1- and beta2-receptors were determined by radioligand binding. BetaARK mRNA levels were increased almost threefold in both forms of heart failure, and betaARK activity was enhanced. Beta1-receptor mRNA levels and beta1-receptor numbers were decreased by approximately 50% in both failing groups, whereas these levels were unaltered for beta2-receptors. There were no differences between dilated and ischemic cardiomyopathy for any of these parameters.Conclusions. In addition to other alterations found in failing hearts, the diminished response to beta-receptor agonists appears to involve the combined effects of enhanced expression of betaARK and reduced expression of beta1-receptors.