Copyright © 2007, European Society of Cardiology
Anti-β1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, 28049 Madrid, Spain
*Corresponding address. Tel.: +34 91 497 4865; fax: +34 91 497 4799. fmayor{at}cbm.uam.es
Objective Antibodies specific for the β1-adrenergic receptor (β1AR) 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 β1AR autoantibodies obtained from DCM patients on extracellular signal-regulated kinase (ERK) activation in murine cardiomyocytes.
Results We find that human β1AR autoantibodies potently stimulate ERK1/2 in cardiac cells by using signalling pathways different from those triggered by the classic β-agonist isoproterenol, also leading to a different pattern of activated ERK subcellular localization. The extent of ERK stimulation by endogenous cardiac β1AR is markedly enhanced in the presence of both β1AR-autoantibodies and isoproterenol. Interestingly, β1AR-autoantibody-mediated ERK activation is not blocked by some βAR antagonists used in the treatment of heart failure.
Conclusions Our results suggest that these antibodies elicit a distinct β1AR active conformation that would lead to the engagement of signaling effectors different from those recruited by classic β-agonists, a finding that could lead to better understanding of DCM pathogenesis and aid in designing diagnostic and therapeutic strategies.
KEYWORDS Adrenergic receptors; Autoantibodies; MAP kinase; Cardiomyopathy; Signal transduction
[1] Current address. Centro Nacional de Investigaciones Cardiovasculares, 28034, Madrid, Spain.
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