We 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.
The 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.
These 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.
我们旨在阐明β1AR-SAP97信号体的动力学及其在导致心力衰竭发展的慢性心脏毒性β1AR-CaMKII信号传导中的潜在作用。
在心力衰竭中检查心脏β1AR-SAP97复合物的完整性。SAP97的心脏特异性缺失被开发用于检查衰老小鼠中的β1AR信号传导,慢性肾上腺素能刺激后,和压力超负荷肥厚性心力衰竭。我们显示β1AR-SAP97信号复合物在心力衰竭中降低。SAP97的心脏特异性缺失会导致衰老依赖性心肌病,并加剧由慢性肾上腺素能刺激和压力超负荷引起的心脏功能障碍。与CaMKII活性升高有关。SAP97的缺失促进β1AR与arrestin2和CaMKII的PKA(蛋白激酶A)依赖性缔合,并开启Epac(cAMP直接激活的交换蛋白)依赖性CaMKII活化,驱动心肌有害的功能和结构重塑。此外,我们已经确定GRK5(G蛋白受体激酶-5)是促进激动剂诱导的SAP97从β1AR解离所必需的.GRK5的心脏缺失可防止肾上腺素能诱导的β1AR-SAP97复合物解离,并增加心脏中的CaMKII活性。
这些数据揭示了SAP97在维持心脏β1AR信号的完整性和有害的心脏GRK5-CaMKII轴中的关键作用,该轴可能在心力衰竭治疗中被靶向。图形摘要:本文提供图形摘要。