Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart.
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 (beta ARK).
METHODS AND RESULTS We have therefore investigated expression of beta ARK 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 beta ARK, beta 1- and beta 2-receptors, and of glyceraldehyde phosphate dehydrogenase and beta-actin as controls were measured by quantitative polymerase chain reactions. In addition, beta ARK enzyme activity assays were performed, and the levels of beta 1- and beta 2-receptors were determined by radioligand binding. beta ARK mRNA levels were increased almost threefold in both forms of heart failure, and beta ARK activity was enhanced. beta 1-Receptor mRNA levels and beta 1-receptor numbers were decreased by approximately 50% in both failing groups, whereas these levels were unaltered for beta 2-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 beta ARK and reduced expression of beta 1-receptors.
- Copyright © 1993 by American Heart Association