Autoimmunity Against the Second Extracellular Loop of β 1 -Adrenergic Receptors Induces β-Adrenergic Receptor Desensitization and Myocardial Hypertrophy In Vivo

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Abstract
—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 (GRK5) expression was found in β rabbits. At 6...