Mechanisms of cardiac sympathetic hyperactivity in chronic heart failure

慢性心力衰竭(CHF)引起的心脏交感神经过度活动与心源性猝死有关 导致慢性心力衰竭患者高死亡率的原因。然而，与心脏相关的潜在机制 CHF状态下的交感神经过度活动尚不清楚。心脏节后交感神经元 星状神经节通过影响去甲肾上腺素(NE)和肾上腺皮质激素的释放来调节心脏功能 神经肽Y(NPY)来自这些神经末梢，支配心脏。钙离子通过电压门控内流 Ca++通道是这些神经元终末释放NE和NPY的关键触发因素。我们最近的研究 研究表明，冠脉CPS神经元的N型钙电流和细胞兴奋性增强 结扎性心力衰竭大鼠，伴有心交感神经功能亢进。基于我们的 初步数据，我们假设慢性心力衰竭介导的炎症细胞因子在CPS神经元中诱发N- 细胞周期蛋白依赖性激酶(CDK5)信号途径激活的钙通道和N型钙通道 然后，激活有助于心力衰竭患者的心脏交感神经过度活动。心肌梗死 CHF和假手术(Sham Surgery)大鼠和小鼠将作为该项目的主要实验工具。 在Sham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(清醒和麻醉大鼠)研究，以评估 这个问题。在特定的目标1中，我们将测量CHF是否增加CPS神经元的N型钙电流 通过心交感神经活动来衡量心力衰竭患者的心交感神经亢进。 从CPS神经末梢体内释放NE和NPY，以及心率变异性。在具体目标2中，我们将测试 慢性心力衰竭时CPS神经元N型钙电流的增加是否会引发心力衰竭时的心律不稳定。在……里面 具体目标3，我们将检测炎性细胞因子-CDK5信号通路是否调节N型 慢性心力衰竭大鼠CPS神经元的钙离子通道。这些研究将进一步加深我们对细胞和 CHF心脏交感神经功能亢进的分子机制还将探讨 改善心脏疾病的潜在治疗药物(N型钙通道阻滞剂和新型抗炎药物) 心力衰竭状态下的交感神经功能和降低死亡率。

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.