Regulation of a cardiac b1AR/SERCA2 complex in heart failure

摘要 b1肾上腺素能受体（b1 AR）的脱敏是心力衰竭（HF）的标志，其中b1 AR在心脏的主要部位。 质膜（PM-b1 AR）发生内吞作用。PM-b1 AR的缺失导致cAMP-PKA活性受损 与HF中射血分数降低相关。尽管几十年来的努力主要是为了恢复 心力衰竭的细胞表面b1 AR信号转导，有效的HF药物治疗仍然是一个未满足的临床 需要的与大多数先前的研究不同，这些研究集中在PM的bAR，积累了bAR信号传导的证据 提示可能与HF有关。我们的目标是揭示一个内部的b1 AR信号， 肌浆网（SR）是调节心脏收缩力的关键，在HF中是脱敏的。我们最近 报告了SR（SR-b1 AR）上的功能性b1 AR池。SR-b1 AR被进入细胞的儿茶酚胺激活， 细胞通过主要有机阳离子转运蛋白3。我们发现，单胺氧化酶A（MAOA），一种酶， 在人类HF中显着增加，负责降解儿茶酚胺。高， MAOA的表达基本上限制了儿茶酚胺对HF中SR-b1 AR的接近，尽管增加了MAOA的表达。 同情心驱使在这个提议中，我们假设1）SR-b1 AR的激活是由MAOA微调的， 增强生理应激中心脏E-C偶联; 2）HF中MAOA表达增加加重 b1 AR信号脱敏，并有助于抑制收缩性。我们认为，MAOA抑制重新- 在衰竭的心肌细胞中使SR-b1 AR信号敏感，并在HF中挽救E-C偶联和心脏收缩力。 我们将采用综合实验方法来验证假设。目标1 MAOA控制访问 儿茶酚胺对SR-b1 AR和心肌收缩力的影响。目标2.心脏b1 AR从PM易位 慢性肾上腺素能刺激下HF的SR。目标3：抑制MAOA拯救SR-b1 AR信号传导 和心力衰竭患者的心肌收缩力。与大多数关注PM上肾上腺素能信号的研究不同，本研究 目的是揭示一种新的局部SR肾上腺素能信号在心脏E-C耦合的调节和目前 MAOA作为一个潜在的治疗靶点，以挽救HF患者的心脏收缩力下降。

Abstract Desensitization of b1-adrenergic receptors (b1ARs) is a hallmark of heart failure (HF), in which b1ARs on the plasma membrane (PM-b1AR) undergo endocytosis. The loss of PM-b1AR leads to impaired cAMP-PKA activity associated with reduced ejection fraction in HF. Despite decades of efforts that have primarily aimed to restore the cell surface b1AR signaling in failing hearts, effective pharmacotherapy for HF remains an unmet clinical need. Distinct from most prior studies that focused on bAR at the PM, accumulating evidence of bAR signaling inside myocyte indicates potential implication in HF. We aim to reveal an internal b1AR signaling at the sarcoplasmic reticulum (SR) critical for regulating cardiac contractility, which is desensitized in HF. We recently reported a pool of functional b1ARs on the SR (SR-b1AR). The SR-b1AR is activated by catecholamines entering cells via primarily organic cation transporter 3. We found that monoamine oxidase A (MAOA), an enzyme responsible for the degradation of catecholamines, is significantly increased in human HF. Thus, the elevated expression of MAOA essentially restricts the access of catecholamines to the SR-b1AR in HF despite increased sympathetic drive. In this proposal, we hypothesize that 1) activation of the SR-b1AR is fine-tuned by MAOA for enhancing cardiac E-C coupling in physiological stress; 2) the increased expression of MAOA in HF exacerbates b1AR signaling desensitization and contributes to depressed contractility. We propose that MAOA inhibition re- sensitizes the SR-b1AR signaling in failing myocytes and rescues E-C coupling and cardiac contractility in HF. We will apply integrated experimental approaches to test the hypotheses. Aim 1 MAOA controls the access of catecholamines to the SR-b1AR and cardiac inotropy. Aim 2. Cardiac b1ARs undergo translocation from the PM to the SR under chronic adrenergic stimulation in HF. Aim 3. Inhibition of MAOA rescues the SR-b1AR signaling and cardiac contractility in HF. Distinct from most studies focusing on adrenergic signaling on the PM, this study aims to unravel a novel local SR adrenergic signaling in the regulation of cardiac E-C coupling and present MAOA as a potential therapeutic target to rescue depressed cardiac contractility in HF.