BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy

缺血性和非缺血性心肌病中的 BDNF TrkB- 和 beta-AR 信号

• 批准号: 9447993
• 负责人: Nazareno Paolocci
• 金额: $ 59.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-11 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447993
• 关键词: Accounting; Acute; Adrenergic Receptor; Adrenergic alpha-Antagonists; Agonist; Animal Model; Attenuated; Binding; Brain-Derived Neurotrophic Factor; Canis familiaris; Cardiac; Cardiac Myocytes; Cells; Chronic; Clinical; Collaborations; Coupled; Data; Dilated Cardiomyopathy; Down-Regulation; Etiology; Fostering; Functional disorder; G protein coupled receptor kinase; Generations; Goals; Heart; Heart Arrest; Heart Diseases; Heart failure; Human; Impairment; Infusion procedures; Injury; Knock-out; Knockout Mice; Left; Left ventricular structure; Metabolic; Metabolism; Metoprolol; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pathologic; Peptides; Phosphotransferases; Physiological; Prevention; Production; Proteins; Relaxation; Research; Signal Transduction; Stress; Symptoms; Testing; Therapeutic; Therapeutic Agents; Transgenic Organisms; Tropomyosin; Up-Regulation; Ventricular; clinically relevant; desensitization; design; functional outcomes; hemodynamics; improved; inhibitor/antagonist; novel; overexpression; pre-clinical; prevent; receptor; research clinical testing; sphingosine 1-phosphate; therapeutic target

Brain-derived neurotrophic factor (BDNF) and its associated, specific tropomyosin related kinase B (TrkB) receptor modulates basal myocardial function and low circulating BDNF levels correlate with worsening of symptoms in heart failure (HF) subjects. Deleting BDNF in myocytes leads to prominent LV dilation at baseline, but basal and stress-stimulated left ventricle (LV) function was never tested in cBDNF-/- mice. Our pilot data suggest that left ventricles from human and experimental HF subjects are massively BDNF depleted. Despite this experimental and clinical evidence, cardiac BDNF/TrkB remains largely understudied. The long-term goal is to determine factors accounting for loss in BDNF/TrkB signal in failing hearts, and mechanisms whereby re- introducing BDNF via TrkB stimulation in BDNF-depleted failing hearts affords protection against ischemic and non-ischemic stress. Here we advance the following three novel hypotheses: 1) that myocardial BDNF generation prevents chronic cardiac decompensation in infarcted hearts, and proper βAR activity is involved in this generation; 2) that direct S1PRs stimulation enhances myocardial BDNF production, preventing LV decompensation in infarcted mice, and that selective β1AR-blockers rescue β3AR down-regulation in post-MI hearts, increasing myocardial BDNF levels via β3-AR/S1PRs signal; 3) that cardiac TrkB stimulation rescues β-AR sensitivity and improves decompensation in a dog model of non-ischemic cardiomyopathy. The rationale for the proposal is that understanding how loss in BDNF/TrkB signal contributes to myocardial adaptation to ischemic or non-ischemic cardiac stress will advance efforts to therapeutically harness this capacity for clinical relevant conditions associated to loss of cardiomyocytes due to ischemic or non-ischemic cardiac diseases. The central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will determine if deleting myocardial BDNF worsens outcome in mice with myocardial infarction, and to test whether TrkB agonists rescues BDNF expression and β-AR sensitivity in infarcted hearts, the latter by inhibited GRK2, the major kinase liable for cardiac β-AR desensitization. In Aim 2, we will test if direct β3-AR or S1PRs stimulation enhances myocardial BDNF content to protect the myocardium against myocardial infarction; In Aim 3, we will test whether the chronic infusion of TrkB agonists rescues LV function in dogs with tachypacing-induced HF via improved myocardial efficiency and restored β-AR sensitivity. The proposed research is significant, because it is expected to foster our understanding of a novel compensatory mechanism, BDNF/TrkB signal that can enable the heart to preserve functional integrity and energetic efficiency in myocardial cells under condition of ischemic or non-ischemic stress, and to determine whether TrkB agonists merit further consideration for clinical testing in HF.

脑源性神经营养因子及其相关的特异性原肌球蛋白相关激酶B 受体调节基础心肌功能和低循环BDNF水平与心力衰竭恶化相关 心衰(HF)受试者的症状。删除心肌细胞中的BDNF会导致基线时显著的左室扩张， 但cBDNF-/-小鼠的基础和应激刺激左心室(LV)功能从未被测试过。我们的试点数据 提示人类和实验性心力衰竭受试者的左心室BDNF大量耗尽。尽管 这一实验和临床证据表明，心脏BDNF/TrkB在很大程度上仍未得到研究。长期目标是 目的：确定心脏衰竭时BDNF/TrkB信号丢失的原因，以及重新激活BDNF/TrkB信号的机制。 通过TrkB刺激在BDNF耗竭的衰竭心脏中引入BDNF提供了对缺血和 非缺血性应激。在这里，我们提出了以下三个新的假设：1)心肌BDNF GENERATE可防止梗塞心脏的慢性心脏失代偿，并参与适当的βAR活性 2)直接刺激S1PRs可增加心肌BDNF的产生，从而预防LV 心肌梗死小鼠的失代偿及选择性β1AR阻滞剂挽救心肌梗死后β3AR下调 心脏，通过β3-AR/S1PR信号增加心肌脑源性神经营养因子水平；3)心脏trkB刺激挽救 β-AR敏感性和改善非缺血性心肌病犬模型的失代偿。 该建议的基本原理是了解BDNF/TrkB信号的丢失如何促进心肌梗死 对缺血性或非缺血性心脏应激的适应将促进从治疗上利用这种能力的努力 有关因缺血或非缺血心脏引起的心肌细胞丢失的临床相关情况 疾病。核心假设将在三个综合的具体目标中得到检验。在目标1中，我们将确定 如果删除心肌BDNF会恶化心肌梗死小鼠的预后，并测试TrkB 激动剂挽救梗死心脏脑源性神经营养因子的表达和β-AR的敏感性，后者通过抑制GRK2， 可能导致心脏β-AR脱敏的主要激酶。在目标2中，我们将测试是否直接刺激β3-AR或S1PR 增加心肌BDNF含量以保护心肌免受心肌梗死；在目标3中，我们将 慢性输注TrkB激动剂能否挽救心动过速所致心力衰竭犬的心功能 改善心肌效率，恢复β-AR敏感性。这项拟议的研究意义重大，因为 它有望促进我们对一种新的补偿机制BDNF/TrkB信号的理解，这种信号可以 使心脏在以下条件下保持心肌细胞的功能完整性和能量效率 缺血性或非缺血性应激，并确定TrkB激动剂是否值得进一步考虑用于临床 在高频下进行测试。