Novel adrenergic mechanisms in heart failure therapy

心力衰竭治疗中的新型肾上腺素能机制

• 批准号: 10285982
• 负责人: John R. Teerlink
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285982
• 关键词: Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Adrenergic beta-Antagonists; Adult; Agonist; Animal Model; Basic Science; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular Diseases; Catecholamines; Cells; Cessation of life; Chronic; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Diagnosis; Disease; Drug Targeting; Epinephrine; Genes; Goals; Healthcare Systems; Heart; Heart failure; Hospitalization; Individual; Knock-out; Knockout Mice; Messenger RNA; Metoprolol; Mission; Modeling; Mus; Muscle Cells; Myocardial Ischemia; Norepinephrine; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Post-Traumatic Stress Disorders; Protein Phosphatase 2A Regulatory Subunit PR53; Publishing; Research; Role; Signal Transduction; System; Systolic heart failure; Testing; Toxic effect; Translations; Treatment Failure; Treatment Protocols; Validation; Ventricular; Veterans; Work; agent orange; antagonist; base; cardioprotection; clinical practice; constriction; heart function; high risk; improved; mortality; mouse model; novel; novel therapeutics; pre-clinical; pressure; programs; receptor; statistics; transcriptome sequencing

Heart failure (HF) is a major clinical problem, with 1 million new cases per year, 1 million annual hospital admissions, a 50% 5-year mortality, and a role in 1 of 8 deaths. Little improvement in these statistics over recent decades indicates that current HF drugs could be improved. A classic feature of HF is elevation of cardiac sympathetic activity and circulating catecholamines, norepinephrine (NE) and epinephrine (EPI). NE and EPI activate 3 types of adrenergic receptors (ARs) on cardiac myocytes, β1, α1A, and α1B. Inhibition of excess, chronic β1 stimulation with beta-blockers is a key HF treatment, but the mechanisms of beta-blockers are incompletely understood, and there are no approved HF drugs that target α1-ARs. The overall goals of this project are to uncover novel adrenergic mechanisms in HF, and to further validate α1A adrenergic agonists as potential new drugs to treat HF. This project builds on 3 important novel findings from recent work. First, published data show that stimulation of an α1A-ERK pathway with drug agonists can treat HF in mouse models. Second, preliminary data suggest that beta-blockers can rescue NE and EPI activation of α1A-ERK cardioprotective signaling in cardiac myocytes. Third, published data show a novel model of ARs in ventricular myocytes, where all cells have the β1 and α1B, but only a 60% subset have the α1A, with high levels in only 20%. The β2 and β3 ARs are mostly absent in myocytes. Published data also show that α1-AR knockout decreases myocyte β1 ARs. These new findings raise several key questions regarding adrenergic mechanisms in HF: First, do beta-blockers work in part by rescuing α1A-ERK cardiorotective signaling by NE and EPI? Second, as a corollary, is the α1A receptor required for cardioprotection by beta-blockers? Third, what happens to myocyte β1 receptors downregulated in HF? Are β1 receptors lost selectively in the myocytes that do not have the α1A, and do α1A receptors protect or maintain β1 receptors? Fourth, if beta-blockers work in part by enhancing α1A-ERK signaling by endogenous NE and EPI, will an exogenous α1A agonist still have efficacy in the presence of a beta-blocker? Four specific aims are proposed to address these key questions: Aim I: Test the hypothesis that beta-blockers rescue α1A-ERK cardioprotective signaling by NE and EPI. We will use isolated ventricular myocytes from wild type (WT) and α1A knockout (KO) mice with HF from pressure overload transverse aortic constriction (TAC), and will examine a PKA-PP2A mechanism. Aim II. Test the hypothesis that cardiac myocyte α1A receptors are required for β-blocker efficacy in heart failure. We will compare beta-blocker rescue of TAC HF in WT and induced cardiac myocyte-specific α1A KO mice. Aim III: Test the hypothesis that α1A receptors protect β1-ARs in heart failure. We will use RT- qPCR to quantify α1A and β1 mRNAs in individual ventricular myocytes from TAC hearts. RNA sequencing will test a cardioprotective gene profile in α1A-expressing myocytes. Aim IV: Test the hypothesis that α1A agonist therapy adds efficacy to beta-blockade in heart failure. We will test the beta-blocker metoprolol in the absence or presence of the specific α1A agonist A61603 in a rescue protocol where treatment is started late after TAC, when cardiac function is reduced. RNA sequencing will test for differences in gene profiles with single and combined therapy. Successful completion of these Aims will uncover new adrenergic mechanisms in HF therapy, will provide crucial preclinical validation of a potential novel HF therapy with an α1A agonist, and will hopefully accelerate the translation to patients.

心力衰竭（HF）是一个主要的临床问题，每年有100万个新病例，每年100万例 医院入院，50％的5年死亡率以及8例死亡中的1名角色。这些统计数据几乎没有改善 近几十年来，目前可以改善HF药物。 HF的一个经典特征是心脏交感神经活动和循环儿茶酚胺的抬高， 去甲肾上腺素（NE）和肾上腺素（EPI）。 NE和EPI激活3种类型的肾上腺素受体（ARS） 心肌细胞β1，α1a和α1b。抑制过量，用β受体阻滞剂刺激慢性β1是关键 HF治疗，但β受体阻滞剂的机制尚不完全理解，并且没有批准 靶向α1-AR的HF药物。该项目的总体目标是发现新颖的肾上腺素机制 HF，​​并进一步验证α1a肾上腺激动剂作为治疗HF的潜在药物。 该项目基于最近工作的3个重要新发现。首先，已发布的数据显示 用药物激动剂刺激α1A-ERK途径可以治疗小鼠模型中的HF。第二，初步 数据表明，β受体阻滞剂可以挽救NE和EPI激活α1A-ERK心脏保护信号传导 心肌细胞。第三，已发表的数据显示了心室肌细胞中ARS的新型模型，所有细胞都 具有β1和α1b，但只有60％的子集具有α1a，只有20％的水平很高。 β2和β3ARS 在心肌细胞中大多不存在。已发布的数据还表明，α1-AR敲除减少了心肌细胞β1AR。 这些新发现提出了有关HF中肾上腺素机制的几个关键问题： 首先，β受体阻滞剂是否部分通过NE和EPI挽救α1A-ERK心形信号传导？ 其次，作为推论，是β受体阻滞剂所需的α1a接收器吗？ 第三，在HF中下调的肌细胞β1受体会发生什么？ β1受体是否有选择地丢失 没有α1a的心肌细胞，α1a受体是否保护或维持β1受体？ 第四，如果β受体阻滞剂部分通过内源性NE和EPI增强α1A-ERK信号传导而起作用，则将 外源α1a激动剂在存在β受体阻滞剂的情况下仍然具有效率？ 提出了四个具体目标来解决以下关键问题： 目的I：测试β受体阻滞剂营救α1A-ERK心脏保护信号的假设 和Epi。我们将使用HF的野生型（WT）和α1A敲除（KO）小鼠的孤立心室肌细胞 从压力过载横向主动脉收缩（TAC）中，将检查PKA-PP2A机制。 目标II。检验以下假设：β受体阻滞剂需要心肌α1A受体 心力衰竭的功效。我们将比较WT中TAC HF的Beta-Blocker Rescue和诱发心脏 心肌细胞特异性α1aKO小鼠。 AIM III：检验α1a受体保护心力衰竭β1-AR的假设。我们将使用RT- QPCR从TAC心脏中量化单个心室肌细胞中的α1a和β1mRNA。 RNA测序 将测试表达α1a的心肌细胞中的心脏保护基因谱。 AIM IV：检验α1a激动剂疗法的假设增加了心脏中β受体阻滞的效率 失败。我们将在不存在或存在特定α1a激动剂的情况下测试β受体阻滞剂美托洛尔 A61603在救援方案中，在TAC降低心脏功能后，在TAC后较晚开始治疗。 RNA 测序将测试单一和联合治疗的基因谱差异。 这些目标的成功完成将发现HF疗法中的新肾上腺素机制，将 用α1A激动剂对潜在的新型HF疗法提供至关重要的临床前验证，并希望 加速对患者的翻译。

项目成果

Coupling to Gq Signaling Is Required for Cardioprotection by an Alpha-1A-Adrenergic Receptor Agonist.

Alpha-1A-肾上腺素能受体激动剂的心脏保护作用需要与 Gq 信号传导偶联。

• DOI: 10.1161/circresaha.118.314416
• 发表时间: 2019
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Myagmar,Bat-Erdene;Ismaili,Taylor;Swigart,PhilipM;Raghunathan,Anaha;Baker,AnthonyJ;Sahdeo,Sunil;Blevitt,JonathanM;Milla,MarcosE;Simpson,PaulC
• 通讯作者: Simpson,PaulC

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice.

• DOI: 10.1371/journal.pone.0168409
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Montgomery MD;Chan T;Swigart PM;Myagmar BE;Dash R;Simpson PC
• 通讯作者: Simpson PC