Anti-beta1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells.
OBJECTIVE
Antibodies specific for the beta1-adrenergic receptor (beta1AR) are highly prevalent in patients with idiopathic dilated cardiomyopathy (DCM) and known to contribute to the pathogenesis of heart failure, though the precise molecular mechanisms involved are largely unknown.


METHODS
We have explored the effects of beta(1)AR autoantibodies obtained from DCM patients on extracellular signal-regulated kinase (ERK) activation in murine cardiomyocytes.


RESULTS
We find that human beta(1)AR autoantibodies potently stimulate ERK1/2 in cardiac cells by using signalling pathways different from those triggered by the classic beta-agonist isoproterenol, also leading to a different pattern of activated ERK subcellular localization. The extent of ERK stimulation by endogenous cardiac beta(1)AR is markedly enhanced in the presence of both beta(1)AR-autoantibodies and isoproterenol. Interestingly, beta(1)AR-autoantibody-mediated ERK activation is not blocked by some betaAR antagonists used in the treatment of heart failure.


CONCLUSIONS
Our results suggest that these antibodies elicit a distinct beta(1)AR active conformation that would lead to the engagement of signaling effectors different from those recruited by classic beta-agonists, a finding that could lead to better understanding of DCM pathogenesis and aid in designing diagnostic and therapeutic strategies.
Tutor
Antonio S
AS
Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Penela
Petronila
P
Mayor
Federico
F
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000494:pharmacology*; D002311:Cardiomyopathy, Dilated / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009206:Myocardium / Q000276:immunology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000276:immunology*; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology*; D013268:Stimulation, Chemical; D014162:Transfection / Q000379:methods
D000318:Adrenergic beta-Agonists; D001323:Autoantibodies; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol