β 1 -Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis

Author:

Jane-wit Daniel1,Altuntas Cengiz Z.1,Johnson Justin M.1,Yong Sandro1,Wickley Peter J.1,Clark Pamela1,Wang Qing1,Popović Zoran B.1,Penn Marc S.1,Damron Derek S.1,Perez Dianne M.1,Tuohy Vincent K.1

Affiliation:

1. From the Departments of Immunology (D.J.-w., C.Z.A., J.M.J., V.K.T.), Molecular Cardiology (S.Y., Q.W., D.M.P.), Anesthesiology Research (P.J.W., D.S.D.), Central Cell Services (P.C.), and Cardiovascular Medicine and Cell Biology (Z.B.P., M.S.P.), Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Abstract

Background— Antibodies to the β 1 -adrenergic receptor (β 1 AR) are detected in a substantial number of patients with idiopathic dilated cardiomyopathy (DCM). The mechanism whereby these autoantibodies exert their pathogenic effect is unknown. Here, we define a causal mechanism whereby β 1 AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM. Methods and Results— We used the β 1 AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the β 1 AR. After transfer into naive male hosts, β 1 AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of β 1 AR IgG before transfer and by selective pharmacological antagonism of host β 1 AR but not β 2 AR. We found that β 1 AR autoantibodies shifted the β 1 AR into the agonist-coupled high-affinity state and activated the canonical cAMP-dependent protein kinase A signaling pathway in cardiomyocytes. These events led to functional alterations in intracellular calcium handling and contractile function. Sustained agonism by β 1 AR autoantibodies elicited caspase-3 activation, cardiomyocyte apoptosis, and DCM in vivo, and these processes were prevented by in vivo treatment with the pan-caspase inhibitor Z-VAD-FMK. Conclusions— Our data show how β 1 AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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