Autoimmunity against the second extracellular loop of β1-adrenergic receptors induces β-adrenergic receptor desensitization and myocardial hypertrophy in vivo

Michikado Iwata, Tsutomu Yoshikawa, Akiyasu Baba, Toshihisa Anzai, Iwao Nakamura, Yumiko Wainai, Toshiyuki Takahashi, Satoshi Ogawa

研究成果: Article査読

71 被引用数 (Scopus)

抄録

Although immunoapheresis removing autoantibodies against the second extracellular domain of β1-adrenergic receptors (ARs) improves cardiac function in patients with cardiomyopathy, the underlying mechanisms have not been defined. We examined the role of autoimmunity against the domain in the development of cardiac dysfunction in vivo. Japanese white rabbits were immunized with a synthetic peptide corresponding to the second extracellular loop of β1-AR once a month with (β + biso rabbits, n= 10) or without (β rabbits, n = 13) bisoprolol treatment (2 mg/kg per day). Control rabbits received vehicle without bisoprolol treatment (n = 13). Autoantibodies of IgG isotype against the domain were persistently detected in β and β + biso rabbits. Purified IgG from sera of β and β + biso rabbits increased cAMP production in a rabbit cardiac membrane preparation, which was blocked by bisoprolol. At 3 months, β-AR uncoupling with increased G protein - coupled receptor kinase 5 (GRKS) expression was found in β rabbits. At 6 months, left ventricular hypertrophy was noted with hemodynamic derangements in β rabbits. This was accompanied by decreased β1-AR density and increased inhibitory G protein and GRK5 expression, which were related to marked decrease in membrane cAMP production. These changes in β rabbits at 6 months were prevented in β + biso rabbits. There was no difference in the plasma norepinephrine concentration in the 3 groups over the observation period. Thus, autoimmunity against the second extracellular loop of β1-ARs induced profound β-AR desensitization and myocardial hypertrophy in vivo, associated with cardiac dysfunction. Sustained sympathomimetic-like actions of autoantibodies against the domain may be partly responsible for these changes.

本文言語English
ページ(範囲)578-586
ページ数9
ジャーナルCirculation research
88
6
DOI
出版ステータスPublished - 2001 3 30

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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