Potential therapies to improve ventricular vagal function in type 2 diabetes

项目摘要 糖尿病引起的心脏迷走神经活动减少与心脏性猝死有关， 糖尿病患者的高死亡率。增加心脏迷走神经张力显著限制心脏 功能障碍并降低死亡率。然而，参与减少的潜在机制 2型糖尿病（T2DM）患者的心脏迷走神经活动知之甚少。心脏迷走神经 神经节神经元（迷走神经控制心脏功能的最终共同途径）调节 乙酰胆碱释放影响心脏功能。电压门控Ca ++内流 通道是从这些神经元末梢释放乙酰胆碱的关键触发器。我们最近 研究表明，心脏迷走神经N型Ca ++通道表达和电流密度 2型糖尿病大鼠神经节细胞减少。大鼠心脏迷走神经节分为 窦房神经节和房室神经节（AVG）。只有心室肌 接收来自AVG神经元的神经末梢的投射。根据初步数据，我们 假设T2DM介导过氧化氢（H2O2）在AVG中过量产生 神经元通过阻遏元件1沉默抑制N型Ca ++通道功能 转录因子（REST）信号传导和/或通过直接作用，其进一步有助于 2型糖尿病患者心室迷走神经功能减弱。利用多方面的技术 从整体动物到细胞分子水平的方法，我们将在体内设计， 在假手术和T2DM大鼠的体外研究中评估这些问题。具体目标1： 通过N型Ca ++测定，说明T2DM是否诱导心室迷走神经元功能障碍 心室肌细胞钙通道表达和激活、细胞兴奋性和细胞内Ca ++水平 迷走神经元，以及从迷走神经末梢释放的心室乙酰胆碱。在 具体目标2，我们将测试H2O2过量产生如何调节AVG神经元的功能， T2DM通过REST信令。在特定目标3中，我们将确定心室功能是否受损 迷走神经元参与T2DM患者的心室电和收缩功能障碍。这些 研究将进一步加深我们对细胞和分子机制的理解， 2型糖尿病患者心脏迷走神经活动受损，并将探索潜在的治疗方法， 心脏迷走神经活动和降低T2DM死亡率。

Project Summary Diabetes-reduced cardiac vagal activity is involved in sudden cardiac death and is responsible for high mortality in diabetic patients. Increasing cardiac vagal tone significantly limits cardiac dysfunction and reduces mortality. However, the potential mechanisms involved in reduced cardiac vagal activity in type 2 diabetes mellitus (T2DM) are poorly understood. Cardiac vagal ganglionic neurons (a final common pathway for vagal control of cardiac function) regulate acetylcholine release to influence cardiac function. Ca++ influx through voltage-gated Ca++ channels is a key trigger for acetylcholine release from these neuronal terminals. Our recent study has shown that expression and current density of N-type Ca++ channels in cardiac vagal ganglionic neurons are decreased in T2DM rats. Rat cardiac vagal ganglia are divided into the sinoatrial ganglion and the atrioventricular ganglion (AVG). The ventricular myocardium only receives the projection of nerve terminals from AVG neurons. Based on our preliminary data, we hypothesize that T2DM-mediated hydrogen peroxide (H2O2) overproduction in AVG neurons inhibits N-type Ca++ channel function via repressor element 1-silencing transcription factor (REST) signaling and/or by direct action, which further contributes to attenuation of ventricular vagal neuronal function in T2DM. Using multi-faceted technical approaches ranging from whole-animals to cellular-molecular levels, we will design in vivo and in vitro studies in sham and T2DM rats to assess these questions. In Specific Aim 1, we will address if T2DM induces ventricular vagal neuronal dysfunction as measured by N-type Ca++ channel expression and activation, cell excitability, and intracellular Ca++ levels in ventricular vagal neurons, as well as ventricular acetylcholine release from vagal nerve terminals. In Specific Aim 2, we will test how H2O2 overproduction modulates function of AVG neurons in T2DM through REST signaling. In Specific Aim 3, we will determine if impairment of ventricular vagal neurons contributes to ventricular electrical and contractile dysfunction in T2DM. These studies will further our understanding of the cellular and molecular mechanisms responsible for impaired cardiac vagal activity in T2DM and will also explore potential therapeutics for improving cardiac vagal activity and reducing mortality in T2DM.