Anti-β1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells

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Abstract

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. © 2007 European Society of Cardiology.

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Tutor, A. S., Penela, P., & Mayor, F. (2007). Anti-β1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells. Cardiovascular Research, 76(1), 51–60. https://doi.org/10.1016/j.cardiores.2007.05.022

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