Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure

慢性心力衰竭心脏交感神经亢进的机制

• 批准号: 9364173
• 负责人: Yu-Long Li
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364173
• 关键词: Action Potentials; Address; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arrhythmia; Calcium Channel; Cardiac; Cells; Clinical; Congestive Heart Failure; Conscious; Coronary artery; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Data; Dexamethasone; Functional disorder; Genetic; Heart; Hyperactive behavior; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Ligation; Link; Measures; Mediating; Microinjections; Molecular; Mus; Myocardial Infarction; Nerve; Neurons; Neurotransmitters; Norepinephrine; Patients; Pharmaceutical Preparations; Polymers; Proteins; Rattus; Regulation; Role; Signal Pathway; Signal Transduction; Structure of stellate ganglion; Sympathetic Nervous System; TNF gene; Testing; Therapeutic; Tissues; Transfection; Ventricular; Ventricular Arrhythmia; base; channel blockers; curative treatments; cytokine; design; effective therapy; heart rate variability; heart rhythm; improved; in vivo; mortality; neuropeptide Y; novel; overexpression; sham surgery; small hairpin RNA; sudden cardiac death; tool; voltage

Chronic heart failure (CHF)-induced cardiac sympathetic overactivity is involved in sudden cardiac death and is responsible for high mortality in patients with CHF. However, the potential mechanisms concerning cardiac sympathetic overactivity in the CHF state are unclear. Cardiac postganglionic sympathetic (CPS) neurons located in stellate ganglia regulate cardiac function by influencing release of norepinephrine (NE) and neuropeptide Y (NPY) from these neuronal terminals innervating the heart. Ca++ influx through voltage-gated Ca++ channels is a key trigger for the release of NE and NPY from these neuronal terminals. Our recent study has shown that N-type Ca++ currents and cell excitability in CPS neurons are enhanced in coronary artery ligation-induced CHF rats, which are accompanied by cardiac sympathetic hyperactivity. Based on our preliminary data, we hypothesize that CHF-mediated inflammation cytokines in CPS neurons evoke N- type Ca++ channel activation via cyclin-dependent kinase (Cdk5) signaling, and N-type Ca++ channel activation then contributes to cardiac sympathetic hyperactivity in CHF. Myocardial infarction-induced CHF and sham (sham surgery) rats and mice will be used as the primary experimental tool in this project. Using multi-faceted technical approaches (from whole-animal to cellular-molecular levels) in sham and CHF rats, we will design in-vitro (cells and tissues) and in-vivo (conscious and anesthetized rats) studies to assess this question. In specific Aim 1, we will measure whether CHF-increased N-type Ca++ currents in CPS neurons contribute to cardiac sympathetic hyperactivity in CHF as measured by cardiac sympathetic nerve activity, in- vivo release of NE and NPY from CPS nerve terminals, and heart rate variability. In Specific Aim 2, we will test whether CHF-increased N-type Ca++ currents in CPS neurons trigger cardiac rhythm instability in CHF. In Specific Aim 3, we will measure whether inflammatory cytokine-Cdk5 signaling pathway modulates N-type Ca++ channels in CPS neurons of CHF rats. These studies will further our understanding of the cellular and molecular mechanisms responsible for the cardiac sympathetic hyperactivity in CHF and will also explore potential therapeutics (N-type Ca++ channel blockers and new anti-inflammatory drugs) for improving cardiac sympathetic function and reducing mortality in the CHF state.

慢性心力衰竭（CHF）诱导的心脏交感神经过度活跃参与心源性猝死， 导致CHF患者的高死亡率。然而，关于心脏的潜在机制 CHF状态下的交感神经过度活跃尚不清楚。心脏节后交感神经元 位于星状神经节，通过影响去甲肾上腺素（NE）的释放来调节心脏功能， 神经肽Y（NPY）从这些神经末梢支配心脏。电压门控Ca++内流 Ca++通道是这些神经元末梢释放NE和NPY的关键触发器。我们最近的研究 已经表明，冠状动脉中CPS神经元的N型Ca++电流和细胞兴奋性增强， 结扎诱导的CHF大鼠，其伴有心脏交感神经功能亢进。基于我们 根据初步数据，我们假设CPS神经元中CHF介导的炎症细胞因子引起N- 通过细胞周期蛋白依赖性激酶（Cdk 5）信号转导激活的N型Ca++通道和N型Ca++通道 激活则导致CHF中的心脏交感神经活动过度。心肌梗死诱发 CHF和假手术（假手术）大鼠和小鼠将用作本项目的主要实验工具。 在假手术和CHF中使用多方面的技术方法（从整体动物到细胞分子水平） 我们将设计体外（细胞和组织）和体内（清醒和麻醉大鼠）研究，以评估 这个问题在具体目标1中，我们将测量CHF是否增加CPS神经元中的N型Ca++电流 通过心脏交感神经活动测量，导致CHF中的心脏交感神经活动过度， 从CPS神经末梢体内释放NE和NPY，以及心率变异性。在第二阶段，我们将测试 CHF增加CPS神经元N型Ca++电流是否触发CHF心律不稳定。在 具体目标3，我们将测量炎症性丝氨酸-Cdk 5信号通路是否调节N型 慢性心力衰竭大鼠CPS神经元钙通道的研究这些研究将进一步加深我们对细胞和 分子机制负责心脏交感神经功能亢进，在CHF，也将探讨 用于改善心脏的潜在治疗剂（N型Ca++通道阻断剂和新的抗炎药） 交感神经功能和降低CHF状态下的死亡率。