GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.
GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.
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GRK5 控制心力衰竭中 SAP97 依赖性心脏毒性β1 肾上腺素受体-CaMKII 信号传导。
DOI：
10.1161/circresaha.119.316319
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发表时间：
2020
影响因子：
20.1
通讯作者：
Nieve
中科院分区：
文献类型：
--
作者：
Xu,Bing;Li,Minghui;Wang,Ying;Zhao,Meimi;Morotti,Stefano;Shi,Qian;Wang,Qingtong;Barbagallo,Federica;Teoh,Jian-Peng;Reddy,GopireddyR;Bayne,ElizabethF;Liu,Yongming;Shen,Ao;Puglisi,JoseL;Ge,Ying;Li,Ji;Grandi,Eleonora;Nieve
心毒性β 1肾上腺素能受体(β1AR)-CaMKII（钙调素依赖性激酶II）信号是与心力衰竭发展相关的主要和关键特征。SAP97（突触相关蛋白97）是一种多功能支架蛋白，直接结合β1AR的c端并组织受体信号体。目的阐明β1AR-SAP97信号体的动力学及其在慢性心脏毒性β1AR-CaMKII信号传导中参与心力衰竭发展的潜在作用。方法与结果检测心力衰竭患者心脏β1AR-SAP97复合物的完整性。研究人员利用SAP97的心脏特异性缺失来检测衰老小鼠、慢性肾上腺素能刺激和压力过载肥厚性心力衰竭后的β1AR信号。我们发现β1AR-SAP97信号复合物在心力衰竭中减少。心脏特异性SAP97缺失会产生一种衰老依赖性心肌病，并加剧慢性肾上腺素能刺激和压力过载引起的心功能障碍，这与CaMKII活性升高有关。SAP97的缺失促进了PKA（蛋白激酶A）依赖性β1AR与arrestin2和CaMKII的关联，并开启了Epac（由cAMP直接激活的交换蛋白）依赖性CaMKII的激活，从而导致心肌有害的功能和结构重塑。此外，我们已经发现GRK5 （g蛋白受体激酶-5）是促进激动剂诱导的SAP97与β1AR分离所必需的。心脏中GRK5的缺失阻止了肾上腺素能诱导的β1AR-SAP97复合物的解离，并增加了心脏中CaMKII的活性。这些数据揭示了SAP97在维持心脏β1AR信号完整性和有害的心脏GRK5-CaMKII轴方面的关键作用，这可能是心力衰竭治疗的潜在靶点。本文提供了一份图形摘要。
RationaleCardiotoxic β1adrenergic 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 AbstractA graphical abstract is available for this article.