Mechanisms of Maladaptation in Heart Failure

Duke University, Durham NC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Abnormalities in the ?-Adrenergic Receptor (?AR) signaling system, such as reduction in the number of ???s (downregulation) and diminished contractile response to catecholamine stimulation (receptor desensitization) are hallmarks of heart failure. However, whether changes in ?AR signaling represent an adaptive protective process, as some postulate, or whether ?AR dysregulation actually promotes deterioration of cardiac function is under considerable debate. Results from our previous studies suggest that chronic ?AR downregulation in the failing heart is indeed maladaptive and contributes to the deterioration in cardiac function. We propose to test the hypothesis that abnormalities in ?AR signaling promote chronic deterioration in cardiac function by activating deleterious signaling pathways in the failing heart. The overall goal of this proposal is to elucidate the mechanisms by which abnormalities in ?ARs leads to maladaptation in heart failure. Accordingly the specific aims are: 1) To define in vitro, the molecular mechanism(s) by which ?ARs mediates transactivation of the Epidermal Growth factor Receptor (EGFR) to produce a growth response; 2) To investigate G-protein independent mechanisms of ?1AR signaling by studying the role of Darrestin and individual GRKs on the transactivation of the EGFR by the ?1AR; 3) To determine whether in vivo, the subtype of ?AR is critical for transactivation of the EGFR in the heart under normal and pressure overload induced heart failure; and 4) To determine the role of specific ?AR subtypes in the development of heart failure using knock out mice that lack each of the ?AR subtypes. Over the past 5 years we have identified new mechanisms for the activation and inactivation of ?AR signaling pathways based on novel protein-protein interactions. This proposal builds on those investigations to advance our understanding of the role ?AR dysfunction plays in the development of heart failure. [unreadable] [unreadable]