Molecular and Cellular Determinants of the Exercise Pressor Reflex in CHF

描述(申请人提供)：慢性心力衰竭(CHF)是美国主要的死亡原因之一。CHF患者的一个特点是在体力活动中交感神经兴奋和运动耐量增加。即使在适度的运动中，交感神经系统的极度激活也经常会导致过度的升压反应和过度换气，这可能会增加这些人在体力活动期间患心血管疾病的风险。 病人。现有证据表明，运动中过度的交感神经兴奋与运动加压反射(EPR)的贡献增加直接相关。然而，CHF患者EPR增加的分子和细胞机制仍有待确定。由于充血性心力衰竭时骨骼肌灌注区的不足，活性氧的释放和炎症可能激活了肌肉传入神经元中的丝裂原活化蛋白激酶(MAPK)通路。我们假设慢性氧化应激在肌肉传入终末启动了CHF肌肉传入神经元MAPK信号通路的激活。这种激活反过来通过影响传入神经元的兴奋性来增加EPR的传入输入。在细胞水平上，我们假设CHF大鼠肌肉传入神经元(DRG‘s)电压门控钠通道(NAV)活动增强有助于传入神经元兴奋性增强和EPR。由于运动训练(EXT)可预防心肌梗死大鼠模型中夸大的EPR，我们认为EXT通过抑制MAPK通路的过度激活而部分地防止EPR的夸大。我们将使用分子(实时荧光聚合酶链式反应、单细胞实时聚合酶链式反应、蛋白质印迹、免疫荧光和体内基因转移)、细胞(膜片钳)和整体动物实验(测量EPR功能、单一传入记录)等高度集成的技术来验证这些假说。我们相信，拟议的研究将解决与充血性心力衰竭患者生活质量直接相关的重要功能和机制问题。此外，我们相信这些数据将揭示CHF治疗的新靶点。

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A hallmark of CHF patients is elevated sympatho-excitation and exercise intolerance during physical activity. Even during moderate exercise, extreme activation of the sympathetic nervous system is often seen causing an exaggerated pressor response and hyperventilation, which potentially increases cardiovascular risk during physical activity in these patients. Existing evidence indicates that the exaggerated sympatho-excitation during exercise is directly related to increased contribution of the exercise pressor reflex (EPR). However, the molecular and cellular mechanisms underlying the increased EPR in CHF remain to be determined. Due to underperfused areas of skeletal muscle in CHF, release of reactive oxygen species and inflammation may activate the mitogen-activated protein kinase (MAPK) pathways in muscle afferent neurons. We hypothesize that chronic oxidative stress in muscle afferent terminals initiate activation of the MAPK signaling pathway in muscle afferent neurons in CHF. This activation, in turn, increases the afferent input of the EPR by affecting afferent neuronal excitability. At the cellular level, we hypothesize that enhanced voltage-gated sodium channel (Nav) activity in muscle afferent neurons (DRG's) of CHF rats contributes to the enhanced afferent neuronal excitability and the EPR. Since exercise training (ExT) prevents the exaggerated EPR in a myocardial infarction rat model we propose that ExT prevents the exaggerated EPR, in part, by inhibition of excessive activation of the MAPK pathway. We will use highly integrative techniques including molecular (real-time PCR, single cell real-time PCR, western blot, immunofluorescence, and in vivo gene transfer), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test these hypotheses. We believe that the proposed research will address important functional and mechanistic issues that directly relate to the quality of life in patients with CHF. Furthermore, w believe that these data will uncover new targets for therapy in CHF.