Molecular and Cellular Determinants of the Exercise Pressor Reflex in CHF

描述（由申请人提供）：慢性心力衰竭（CHF）是美国主要的死亡原因之一。CHF患者的一个标志是身体活动期间交感神经兴奋和运动不耐受升高。即使在适度运动期间，也经常看到交感神经系统的极度激活，导致过度的升压反应和过度通气，这可能会增加这些人在体力活动期间的心血管风险。 患者现有证据表明，运动时交感神经兴奋过度与运动加压反射（EPR）的贡献增加直接相关。然而，CHF中EPR增加的分子和细胞机制仍有待确定。由于CHF时骨骼肌灌注不足，活性氧的释放和炎症可能激活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末梢启动激活MAPK信号通路在肌肉传入神经元在CHF。这种激活反过来又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）的电压门控钠通道（Nav）活性增强有助于增强传入神经元的兴奋性和EPR。由于运动训练（ExT）防止夸大的EPR在心肌梗死大鼠模型中，我们建议ExT防止夸大的EPR，在某种程度上，通过抑制MAPK通路的过度激活。我们将使用高度整合的技术，包括分子（实时PCR，单细胞实时PCR，蛋白质印迹，免疫荧光和体内基因转移），细胞（膜片钳）和整个动物实验（测量EPR功能，单传入记录）来验证这些假设。我们相信，拟议的研究将解决重要的功能和机制的问题，直接关系到CHF患者的生活质量。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.