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 (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.