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Regulation of a cardiac b1AR/SERCA2 complex in heart failure

心力衰竭中心脏 b1AR/SERCA2 复合物的调节

基本信息

批准号：
10641923
负责人：
Manuel F Navedo
金额：
$ 63.17万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641923
关键词：
ATP2A2 Acute Adrenergic Agents Adrenergic Receptor Affect Attenuated Biosensor Calcium Cardiac Catecholamines Cell membrane Cell surface Cells Chronic Clinical Complex Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Depressed mood EFRAC Endocytosis Enzymes Fluorescence Resonance Energy Transfer Genetic Heart Heart failure Human Impairment In Vitro Infusion procedures Monoamine Oxidase A Mus Muscle Cells Organic Cation Transporter Pharmacotherapy Phosphorylation Physiological Receptor Activation Receptor Signaling Regulation Reporting Resistance Sarcoplasmic Reticulum Scheme Signal Transduction Stress Testing United States access restrictions aorta constriction desensitization heart function in vivo monoamine mortality mouse model novel overexpression pharmacologic phospholamban public health relevance receptor response sarcoplasmic reticulum calcium ATPase therapeutic target

项目摘要

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.

摘要 B1-肾上腺素能受体(B1ARs)的脱敏是心力衰竭(HF)的一个标志。质膜(PM-b1AR)经历内吞作用。PM-b1AR的缺失导致cAMP-PKA活性受损与心衰时射血分数降低有关。尽管几十年的努力主要是为了恢复心力衰竭时细胞表面b1AR信号转导机制的研究，有效的药物治疗仍未达到临床效果需要。不同于之前大多数集中在下午BAR的研究，积累了BAR信号的证据心肌细胞内提示心力衰竭的潜在意义。我们的目标是揭示内部b1AR信号在肌浆网(SR)是调节心肌收缩能力的关键物质，在HF中是不敏感的。我们最近已报告SR(SR-b1AR)上工作正常的b1AR池。儿茶酚胺可以激活SR-b1AR 细胞主要通过有机阳离子转运蛋白3。我们发现单胺氧化酶A(MAOA)，一种酶负责降解儿茶酚胺，在人类心力衰竭中显著增加。因此，被提升的 MAOA的表达本质上限制了儿茶酚胺对SR-b1AR的访问，尽管增加了同情心的驱动力。在这个建议中，我们假设1)SR-b1AR的激活是由MAOA微调的生理性应激增强心脏E-C偶联；2)心力衰竭时MAOA表达增加加剧 B1AR信号失敏，导致收缩功能受抑。我们认为，MAOA的抑制作用可能与其相互作用有关。在衰竭的心肌细胞中敏化SR-b1AR信号，挽救心衰时的E-C偶联和心肌收缩能力。我们将使用综合的实验方法来检验这些假设。目标1 MAOA控制访问儿茶酚胺对SR-b1AR和心脏变力作用的影响。目的2.心脏b1AR从PM移位在慢性肾上腺素能刺激下，心衰时对SR的影响。目的3.抑制MAOA挽救SR-b1AR信号转导和心力衰竭时的心肌收缩能力。与大多数专注于PM上的肾上腺素能信号的研究不同，这项研究旨在揭示一种新的局部SR肾上腺素能信号在心脏E-C偶联调节中的作用 MAOA作为一种潜在的治疗靶点来挽救心力衰竭患者低迷的心肌收缩能力。