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GRK5 Controls SAP97-Dependent Cardiotoxic β 1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.

Authors :
Xu B
Li M
Wang Y
Zhao M
Morotti S
Shi Q
Wang Q
Barbagallo F
Teoh JP
Reddy GR
Bayne EF
Liu Y
Shen A
Puglisi JL
Ge Y
Li J
Grandi E
Nieves-Cintron M
Xiang YK
Source :
Circulation research [Circ Res] 2020 Aug 28; Vol. 127 (6), pp. 796-810. Date of Electronic Publication: 2020 Jun 08.
Publication Year :
2020

Abstract

Rationale: Cardiotoxic β <subscript>1</subscript> adrenergic receptor (β <subscript>1</subscript> AR)-CaMKII (calmodulin-dependent kinase II) signaling is a major and critical feature associated with development of heart failure. SAP97 (synapse-associated protein 97) is a multifunctional scaffold protein that binds directly to the C-terminus of β <subscript>1</subscript> AR and organizes a receptor signalosome.<br />Objective: We aim to elucidate the dynamics of β <subscript>1</subscript> AR-SAP97 signalosome and its potential role in chronic cardiotoxic β <subscript>1</subscript> AR-CaMKII signaling that contributes to development of heart failure.<br />Methods and Results: The integrity of cardiac β <subscript>1</subscript> AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine β <subscript>1</subscript> AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β <subscript>1</subscript> AR-SAP97 signaling complex is reduced in heart failure. Cardiac-specific deletion of SAP97 yields an aging-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA (protein kinase A)-dependent association of β <subscript>1</subscript> AR with arrestin2 and CaMKII and turns on an Epac (exchange protein directly activated by cAMP)-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 (G-protein receptor kinase-5) is necessary to promote agonist-induced dissociation of SAP97 from β <subscript>1</subscript> AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β <subscript>1</subscript> AR-SAP97 complex and increases in CaMKII activity in hearts.<br />Conclusions: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac β <subscript>1</subscript> AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy. Graphical Abstract: A graphical abstract is available for this article.

Details

Language :
English
ISSN :
1524-4571
Volume :
127
Issue :
6
Database :
MEDLINE
Journal :
Circulation research
Publication Type :
Academic Journal
Accession number :
32507058
Full Text :
https://doi.org/10.1161/CIRCRESAHA.119.316319