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).


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.
Laboratorium für Molekulare Biologie, Universität München, Max-Planck-Institut für Biochemie, Martinsried, FRG.
M
M
Ungerer
M
M
Böhm
J S
JS
Elce
E
E
Erdmann
M J
MJ
Lohse
D000328:Adult; D001483:Base Sequence; D001667:Binding, Competitive; D002118:Calcium / Q000494:pharmacology; D002303:Cardiac Output, Low / Q000378:metabolism* / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003327:Coronary Disease / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D015345:Oligonucleotide Probes / Q000235:genetics; D010210:Papillary Muscles / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D007545:Isoproterenol; D002118:Calcium