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

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.