Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis.
BACKGROUND
Antibodies to the beta1-adrenergic receptor (beta1AR) 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 beta1AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM.


RESULTS
We used the beta1AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the beta1AR. After transfer into naive male hosts, beta1AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of beta1AR IgG before transfer and by selective pharmacological antagonism of host beta1AR but not beta2AR. We found that beta1AR autoantibodies shifted the beta1AR 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 beta1AR 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 beta1AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.
Jane-wit
Daniel
D
Department of Immunology, NB30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.
Altuntas
Cengiz Z
CZ
Johnson
Justin M
JM
Yong
Sandro
S
Wickley
Peter J
PJ
Clark
Pamela
P
Wang
Qing
Q
Popović
Zoran B
ZB
Penn
Marc S
MS
Damron
Derek S
DS
Perez
Dianne M
DM
Tuohy
Vincent K
VK
D000318:Adrenergic beta-Agonists / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001323:Autoantibodies / Q000097:blood / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology*
D000318:Adrenergic beta-Agonists; D001323:Autoantibodies; D018342:Receptors, Adrenergic, beta-1