Potential therapies to improve ventricular vagal function in type 2 diabetes

项目摘要 糖尿病心脏迷走神经活动减少与心源性猝死有关 糖尿病患者的高死亡率。心脏迷走神经张力增加显著限制心脏 功能障碍，降低死亡率。然而，涉及的潜在机制减少了 对2型糖尿病(T2 DM)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 乙酰胆碱的释放影响心脏功能。通过电压门控机箱的钙离子内流 通道是这些神经元终末释放乙酰胆碱的关键触发因素。我们最近 研究表明，N型钙通道在心脏迷走神经中的表达和电流密度 T2 DM大鼠神经节细胞减少。大鼠心脏迷走神经节分为迷走神经节 窦房结和房室结(AVG)。仅限室壁心肌 从AVG神经元接受神经末梢的投射。根据我们的初步数据，我们 T2 DM介导的AVG中过氧化氢(H_2O_2)过量产生的假说 神经元通过抑制元件1沉默抑制N型钙通道功能 转录因子(REST)信号和/或直接作用，这进一步有助于 2型糖尿病患者的室迷走神经功能减退使用多方面的技术 从整个动物到细胞-分子水平的方法，我们将在体内设计和 对假手术和T2 DM大鼠的体外研究来评估这些问题。在具体目标1中，我们将 2型糖尿病是否导致N型脑室迷走神经功能障碍 心室肌细胞通道表达和激活、细胞兴奋性和细胞内钙水平 迷走神经细胞，以及从迷走神经末梢释放的脑室乙酰胆碱。在……里面 具体目标2，我们将测试H_2O_2过量产生如何调节AVG神经元的功能 T2 DM通过REST信号传递。在特定的目标3中，我们将确定脑室损伤 迷走神经参与了T2 DM患者的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 T2 DM患者心脏迷走神经活动受损，并将探索改善的潜在治疗方法 2型糖尿病心脏迷走神经活动与降低死亡率。

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.