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Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization

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Beatrice Bornholz, Stefanie Weidtkamp-Peters, Stephanie Schmitmeier, Claus A. M. Seidel, Lars R. Herda, Stephan B. Felix, Horst Lemoine, Jürgen Hescheler, Filomain Nguemo, Christoph Schäfer, Morten O. Christensen, Christian Mielke, Fritz Boege
DOI: http://dx.doi.org/10.1093/cvr/cvs350 472-480 First published online: 3 December 2012

Abstract

Aims Autoantibodies against second extracellular loops of β1-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function.

Methods and results IgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β1-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed.

Conclusions (i) Autoantibodies trigger conformation changes in the β1-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels.

  • β1-Adrenergic receptors
  • Receptor conformation
  • Autoantibodies
  • Dilated cardiomyopathy
  • Human embryonic cardiomyocytes

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