1. GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failure
- Author
-
Xu, Bing, Li, Minghui, Wang, Ying, Zhao, Meimi, Morotti, Stefano, Shi, Qian, Wang, Qingtong, Barbagallo, Federica, Teoh, Jian-Peng, Reddy, Gopireddy R, Bayne, Elizabeth F, Liu, Yongming, Shen, Ao, Puglisi, Jose L, Ge, Ying, Li, Ji, Grandi, Eleonora, Nieves-Cintron, Madeline, and Xiang, Yang K
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Cardiovascular ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Cells ,Cultured ,Cyclic AMP-Dependent Protein Kinases ,Discs Large Homolog 1 Protein ,Disease Models ,Animal ,Excitation Contraction Coupling ,G-Protein-Coupled Receptor Kinase 5 ,Guanine Nucleotide Exchange Factors ,Heart Failure ,Humans ,Male ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myocardial Contraction ,Myocytes ,Cardiac ,Receptors ,Adrenergic ,beta-1 ,beta-Arrestin 1 ,calmodulin ,heart failure ,myocyte ,cardiac ,myocardium ,signaling pathways ,myocyte ,cardiac ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
RationaleCardiotoxic β1 adrenergic receptor (β1AR)-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 β1AR and organizes a receptor signalosome.ObjectiveWe aim to elucidate the dynamics of β1AR-SAP97 signalosome and its potential role in chronic cardiotoxic β1AR-CaMKII signaling that contributes to development of heart failure.Methods and resultsThe integrity of cardiac β1AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine β1AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β1AR-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 β1AR 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 β1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β1AR-SAP97 complex and increases in CaMKII activity in hearts.ConclusionsThese data reveal a critical role of SAP97 in maintaining the integrity of cardiac β1AR 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.
- Published
- 2020