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-肾上腺素受体（B1AR）的脱敏是心力衰竭的标志（HF），其中B1AR在该标志上质膜（PM-B1AR）患有内吞作用。 PM-B1AR的损失导致营地PKA活动受损与HF中的射血分数减少有关。尽管数十年的努力主要旨在恢复心脏失败的细胞表面B1AR信号传导，HF的有效药物疗法仍然是未经临床的需要。与大多数集中在PM处的BAR的研究不同，累积了条形信号的证据心肌内部表示HF的潜在影响。我们旨在在肌质网（SR）对于调节心脏收缩性至关重要，这在HF中脱敏。我们最近报告了SR（SR-B1AR）上的功能性B1AR池。 SR-B1AR通过进入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），一种酶负责儿茶酚胺降解的人，在人HF中显着增加。因此，高架尽管增加同情驱动器。在此提案中，我们假设1）MAOA对SR-B1AR的激活进行了微调在生理压力下增强心脏E-C耦合； 2）HF恶化中MAOA的表达增加 B1AR信号传导脱敏并导致收缩性降低。我们建议MAOA抑制作用在肌细胞失败中敏感SR-B1AR信号传导，并在HF中挽救E-C耦合和心脏收缩率。我们将采用综合实验方法来检验假设。 AIM 1 MAOA控制访问 SR-B1AR和心脏障碍的儿茶酚胺。 AIM2。心脏B1ARS从PM易位在HF中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 HF中的心脏收缩性。与大多数关注PM肾上腺素能信号传导的研究不同，本研究旨在在心脏E-C耦合调节中揭示新的局部SR肾上腺素能信号传导 MAOA是HF中挽救抑郁型心脏收缩性的潜在治疗靶标。