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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：
10539066
负责人：
Manuel F Navedo
金额：
$ 62.97万
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/10539066
关键词：
ATP2A2 Acute Adrenergic Agents Adrenergic Receptor Affect Attenuated Biosensor Ca(2+)-Transporting ATPase 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 Intuition Monoamine Oxidase A Mus Muscle Cells Organic Cation Transporter Pharmacology Pharmacotherapy Phosphorylation Physiological Regulation Reporting Resistance Sarcoplasmic Reticulum Scheme Signal Transduction Stress Testing United States constriction desensitization heart function in vivo monoamine mortality mouse model novel overexpression 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.

抽象的 b1 肾上腺素能受体 (b1AR) 脱敏是心力衰竭 (HF) 的一个标志，其中 b1AR 位于质膜 (PM-b1AR) 进行内吞作用。 PM-b1AR 的缺失导致 cAMP-PKA 活性受损与 HF 射血分数降低有关。尽管几十年来的努力主要旨在恢复衰竭心脏中的细胞表面 b1AR 信号传导，有效治疗心力衰竭的药物治疗仍然是一个未满足的临床问题需要。与之前大多数关注 PM 时 bAR 的研究不同，积累了 bAR 信号传导的证据肌细胞内部表明对心力衰竭有潜在影响。我们的目标是揭示内部 b1AR 信号传导肌浆网 (SR) 对于调节心肌收缩力至关重要，而心力衰竭时心肌收缩力不敏感。我们最近报告了 SR 上的功能 b1AR 池 (SR-b1AR)。 SR-b1AR 被进入的儿茶酚胺激活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，在人心力衰竭中显着增加。因此，升高的 MAOA 的表达本质上限制了心力衰竭中儿茶酚胺与 SR-b1AR 的接触，尽管同情的驱动力。在这个提议中，我们假设 1) SR-b1AR 的激活通过 MAOA 进行微调增强生理应激中的心脏 E-C 耦合； 2) 心力衰竭中 MAOA 表达增加加剧 b1AR 信号脱敏并导致收缩力下降。我们建议 MAOA 抑制重新使衰竭心肌细胞中的 SR-b1AR 信号变得敏感，并挽救心力衰竭中的 E-C 耦合和心肌收缩力。我们将应用综合实验方法来检验假设。目标 1 MAOA 控制访问儿茶酚胺对 SR-b1AR 和强心力的影响。目标 2. 心脏 b1AR 从 PM 发生易位 HF 慢性肾上腺素能刺激下的 SR。目标 3. 抑制 MAOA 可挽救 SR-b1AR 信号传导和心衰时的心肌收缩力。与大多数关注 PM 上肾上腺素信号传导的研究不同，本研究旨在解开调节心脏 E-C 耦合的新型局部 SR 肾上腺素信号传导，并提出 MAOA 作为挽救心衰患者心肌收缩力下降的潜在治疗靶点。