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

基本信息

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
项目类别：
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

项目摘要

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）引起的心脏交感神经过度活跃与心源性猝死有关，并且是是CHF患者高死亡率的原因。然而，有关心脏的潜在机制 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 (CPS) 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来自这些神经元末梢的神经肽 Y (NPY) 支配心脏。 Ca++ 通过电压门控流入 Ca++ 通道是这些神经元末梢释放 NE 和 NPY 的关键触发器。我们最近的研究表明冠状动脉中 N 型 Ca++ 电流和 CPS 神经元的细胞兴奋性增强结扎诱导的 CHF 大鼠，伴有心脏交感神经亢进。基于我们的根据初步数据，我们假设 CPS 神经元中 CHF 介导的炎症细胞因子会诱发 N- 通过细胞周期蛋白依赖性激酶 (Cdk5) 信号传导激活 Ca++ 型通道和 N 型 Ca++ 通道然后，激活会导致 CHF 患者的心脏交感神经过度活跃。心肌梗死诱发 CHF和sham（假手术）大鼠和小鼠将被用作该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）大鼠，我们将设计体外（细胞和组织）和体内（清醒和麻醉的大鼠）研究来评估这个问题。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 患者的心脏交感神经过度活跃， CPS 神经末梢体内 NE 和 NPY 的释放以及心率变异性。在具体目标 2 中，我们将测试 CHF 增加的 CPS 神经元 N 型 Ca++ 电流是否会引发 CHF 心律不稳定。在具体目标3，我们将测量炎症细胞因子-Cdk5信号通路是否调节N型 CHF 大鼠 CPS 神经元中的 Ca++ 通道。这些研究将进一步加深我们对细胞和负责 CHF 心脏交感神经亢进的分子机制，还将探索改善心脏功能的潜在疗法（N 型 Ca++ 通道阻滞剂和新型抗炎药）交感神经功能并降低 CHF 状态下的死亡率。