Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces beta-adrenergic receptor desensitization and myocardial hypertrophy in vivo.
Although immunoapheresis removing autoantibodies against the second extracellular domain of beta(1)-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 beta(1)-AR once a month with (beta+biso rabbits, n=10) or without (beta 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 beta and beta+biso rabbits. Purified IgG from sera of beta and beta+biso rabbits increased cAMP production in a rabbit cardiac membrane preparation, which was blocked by bisoprolol. At 3 months, beta-AR uncoupling with increased G protein-coupled receptor kinase 5 (GRK5) expression was found in beta rabbits. At 6 months, left ventricular hypertrophy was noted with hemodynamic derangements in beta rabbits. This was accompanied by decreased beta(1)-AR density and increased inhibitory G protein and GRK5 expression, which were related to marked decrease in membrane cAMP production. These changes in beta rabbits at 6 months were prevented in beta+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 beta(1)-ARs induced profound beta-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.
Iwata
M
M
Cardiology Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Yoshikawa
T
T
Baba
A
A
Anzai
T
T
Nakamura
I
I
Wainai
Y
Y
Takahashi
T
T
Ogawa
S
S
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000235:genetics; D015153:Blotting, Western; D006332:Cardiomegaly / Q000276:immunology / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000276:immunology*; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D007074:Immunoglobulin G; D010446:Peptide Fragments; D018342:Receptors, Adrenergic, beta-1; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins; D007545:Isoproterenol