Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart.

TLDR

In chronic heart failure, beta‑adrenergic receptor agonists elicit diminished positive inotropic effects due to receptor uncoupling and downregulation, the former being driven by phosphorylation by beta‑adrenergic receptor kinase. The study aimed to assess the expression of beta‑adrenergic receptor kinase and beta‑adrenergic receptors in left ventricular tissue from patients with dilated or ischemic cardiomyopathy compared with non‑failing controls. Researchers quantified beta‑ARK, beta‑1, and beta‑2 receptor mRNA by quantitative PCR, measured beta‑ARK enzymatic activity, and determined receptor densities using radioligand binding assays. Failing hearts showed markedly reduced beta‑adrenergic contractile responses, with beta‑ARK mRNA and activity tripled and beta‑1 receptor mRNA and density halved, while beta‑2 receptors remained unchanged, indicating that enhanced beta‑ARK expression and loss of beta‑1 receptors underlie the impaired agonist response.

Abstract

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.