The IgG3 subclass of β1-adrenergic receptor autoantibodies is an endogenous biaser of β1AR signaling

β1-Adrenergic receptor autoantibodies are associated with deleterious consequences; however, the IgG3 subclass provides beneficial outcomes in human heart failure. IgG3 β1AR autoantibody inhibits G-protein coupling, simultaneously activating ERK through G-protein–independent arrestin-dependent mechanisms.

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Abstract 469: Targeting Beta Adrenergic Receptor Resensitization Aids in Preservation of Receptor Function

Circulation Research ◽

10.1161/res.121.suppl_1.469 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Elizabeth E Martellli ◽

Yu Sun ◽

John George ◽

Maradumane L Mohan ◽

Randall Starling ◽

...

Keyword(s):

Heart Failure ◽

Small Molecule ◽

In Silico ◽

Adrenergic Receptor ◽

Human Heart ◽

Receptor Function ◽

Human Heart Failure ◽

Pp2a Activity ◽

Pi3k Activity ◽

Underlying Mechanisms

Beta adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and is an integral contributor to heart failure. We have previously shown that resensitization is regulated by inhibition of PP2A by I2PP2A via PI3Kγ (Vasudevan et. al., 2011), the underlying mechanisms of I2PP2A binding to PP2A are not well understood. We used PyMOL software to find the binding interaction between PP2A and I2PP2A. Based on in silico predictions, we generated a mutant PP2A that when expressed would compete out I2PP2A and inhibit I2PP2A from binding to endogenous PP2A. Expression of PP2A mutant in β2AR expressing cells showed preservation of β2AR function following stimulation as measured by reduced β2AR phosphorylation, increased cAMP generation and increased phosphatase function. We also generated a small molecule from our in silico predictions that could target the interface of I2PP2A and PP2A binding to find that disruption of the PP2A/I2PP2A interaction underlies receptor function. We will use this small molecule to look at preservation of βAR function and amelioration of cardiac function. To test whether resensitization is altered in heart failure we used plasma membrane and endosomal fractions from non-failing and paired pre- and post-LVAD samples to show PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase activity as a measure of recovery in βAR function. Our studies showed that endosomal fractions from human heart failure samples had elevated PI3K activity associated with reduced PP2A activity supporting the idea that βAR resensitization is inhibited in human heart failure samples. Since human heart failure samples have inhibited resensitization we tested the underlying mechanisms regulating βAR resensitization. Thus ongoing studies suggest that targeting the resensitization of βAR could provide beneficial cardiac remodeling in conditions of chronic mechanical overload and will be further discussed.

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