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（Trk B） 受体调节基础心肌功能，低循环BDNF水平与 心力衰竭（HF）患者的症状。删除肌细胞中的BDNF导致基线时显著的LV扩张， 但从未在cBDNF-/-小鼠中测试过基础和应激刺激的左心室（LV）功能。我们的试点数据 提示人和实验性HF受试者的左心室大量BDNF耗竭。尽管 根据实验和临床证据，心脏BDNF/TrkB仍然在很大程度上研究不足。长期目标是 以确定导致心力衰竭时BDNF/TrkB信号丢失的因素，以及重新激活BDNF/TrkB的机制。 通过TrkB刺激在BDNF耗尽的衰竭心脏中引入BDNF提供了针对缺血和缺血性疾病的保护， 非缺血性应激。在此，我们提出了以下三个新的假设：1）心肌BDNF β-肾上腺素能受体的产生可以防止梗死心脏的慢性心脏代偿失调， 在这一代中; 2）直接S1 PRs刺激增强心肌BDNF产生，防止LV 选择性β 1 AR阻断剂可挽救MI后β 3 AR下调 心脏，通过β3-AR/S1 PRs信号增加心肌BDNF水平; 3）心脏TrkB刺激拯救 β-AR敏感性和改善非缺血性心肌病犬模型的失代偿。 该提案的基本原理是，了解BDNF/TrkB信号的丢失如何有助于心肌梗死。 对缺血性或非缺血性心脏应激的适应将促进在治疗上利用这种能力的努力 对于与由于缺血性或非缺血性心脏病引起的心肌细胞损失相关的临床相关病症， 疾病将在三个综合具体目标中检验中心假设。在目标1中，我们将确定 如果删除心肌BDNF会影响心肌梗死小鼠的结局，并测试TrkB是否 激动剂可挽救梗死心脏的BDNF表达和β-AR敏感性，后者通过抑制GRK 2， 主要激酶易导致心脏β-AR脱敏。在目标2中，我们将测试直接β3-AR或S1 PRs刺激是否 增加心肌BDNF含量，保护心肌免受心肌梗死;在目标3中，我们将 测试TrkB激动剂的慢性输注是否通过以下方式挽救患有快速起搏诱导的HF的犬的LV功能： 改善心肌效率，恢复β-AR敏感性。这项研究意义重大，因为 它有望促进我们对一种新的补偿机制的理解，BDNF/TrkB信号， 使心脏在心肌细胞中保持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HF中测试