EXPRESSION OF BETA-ARRESTINS AND BETA-ADRENERGIC-RECEPTOR KINASES IN THE FAILING HUMAN HEART

The beta-adrenergic receptor system of the failing human heart is mark edly desensitized. We have recently postulated that this desensitizati on may in part be caused by an increase in beta-adrenergic receptor ki nase (beta ARK) expression. beta ARK is thought to effect desensitizat ion by acting in concert with an inhibitor protein, called beta-arrest in. Two isoforms have been identified both for beta ARK and for beta-a rrestin. In the present study, we have investigated the expression of the individual isoforms of beta-arrestin and of beta ARK in left ventr icles from failing and control human hearts. mRNAs for all four protei ns, beta-arrestin-1, beta-arrestin-2, beta ARK-1, and beta ARK-2, were identified in human heart. Quantitation by reverse-transcription poly merase chain reactions showed that in heart failure there were no chan ges of the mRNA levels for beta-arrestin-1 and beta-arrestin-2, a slig ht (<50%) increase of the mRNA for beta ARK-2, and a threefold increas e for beta ARK-1 mRNA. At the protein level, beta-arrestin-l was readi ly detected by Western blotting in human heart. Its absolute values we re approximate to 350 fmol/mg cytosolic protein, and its expression wa s not changed in heart failure. beta-Arrestin-2 levels were too low to be detectable using the same methods. beta ARK levels as determined b y enzymatic activity were approximate to 20 fmol/mg cytosolic protein (beta ARK-1 plus beta ARK-2) and thus almost 20-fold lower than those of beta-arrestin. beta ARK levels were increased approximately twofold in heart failure. We hypothesize that, because of its low expression, beta ARK may be the limiting component in beta-adrenergic receptor de sensitization in the human heart and that upregulation of beta ARK-1 e xpression in heart failure may, therefore, play a major role in the de sensitization of these receptors.