| First Author | Xu B | Year | 2020 |
| Journal | Circ Res | Volume | 127 |
| Issue | 6 | Pages | 796-810 |
| PubMed ID | 32507058 | Mgi Jnum | J:317675 |
| Mgi Id | MGI:6856404 | Doi | 10.1161/CIRCRESAHA.119.316319 |
| Citation | Xu B, et al. (2020) GRK5 Controls SAP97-Dependent Cardiotoxic beta1 Adrenergic Receptor-CaMKII Signaling in Heart Failure. Circ Res 127(6):796-810 |
| abstractText | RATIONALE: Cardiotoxic beta1 adrenergic receptor (beta1AR)-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 beta1AR and organizes a receptor signalosome. OBJECTIVE: We aim to elucidate the dynamics of beta1AR-SAP97 signalosome and its potential role in chronic cardiotoxic beta1AR-CaMKII signaling that contributes to development of heart failure. METHODS AND RESULTS: The integrity of cardiac beta1AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine beta1AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the beta1AR-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 beta1AR 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 beta1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of beta1AR-SAP97 complex and increases in CaMKII activity in hearts. CONCLUSIONS: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac beta1AR 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. |
