Neural Inflammation and Exercise Pressor Reflex in Heart Failure

心力衰竭中的神经炎症和运动升压反射

基本信息

批准号：
10712202
负责人：
Hanjun Wang
金额：
$ 62.82万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-16 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10712202
关键词：
Acute Acute Lung Injury Address Afferent Neurons American Animal Experiments Animals Anti-Inflammatory Agents Brain-Derived Neurotrophic Factor Capsaicin Cardiovascular Abnormalities Cardiovascular Physiology Cardiovascular system Cause of Death Cells Characteristics Chronic Clinical Research Coculture Techniques Congestive Heart Failure Data Deterioration Disease Exercise Exercise Tolerance Female Femur Fiber Functional disorder Ganglia Glutamate Transporter Glutamates Goals Heart Rate Heart failure Human Hyperventilation Immunofluorescence Immunologic In Vitro Infiltration Inflammatory Intra-Arterial Injections Ion Channel Limb structure Lipopolysaccharides Macrophage Macrophage Activation Measures Mechanics Mediating Metabolic Modeling Molecular Mus Muscle Myocardial Infarction Nerve Neurons Nociceptors Patch-Clamp Techniques Pathologic Patients Phenotype Physical activity Play Potassium Prostaglandin-Endoperoxide Synthase Quality of life Rattus Reflex action Regulation Reporter Reporting Research Rest Role Signal Pathway Signal Transduction Spinal Ganglia Structure of stellate ganglion Sympathetic Nervous System TRPV1 gene Techniques Testing Time Tissues Vanilloid Vesicle Western Blotting arm cardiovascular risk factor design exercise capacity exercise intolerance experimental study glutamatergic signaling in vivo male mouse model neural neuroinflammation neuronal excitability neuroregulation new therapeutic target patch clamp patient population pharmacologic pressure protein expression receptor respiratory response therapy development ventilation vesicular glutamate transporter 1 voltage

项目摘要

Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A primary characteristic of this disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise pressor reflex (EPR); 2) the enhanced mechanically sensitive afferent component of this reflex (i.e. mechanoreflex) primarily contributes to the exaggerated EPR in CHF and 3) muscle metaboreflex activated by femoral intra-arterial injection of capsaicin is blunted in CHF rats, which is associated with downregulated Transient Receptor Potential Vanilloid Type 1 (TRPV1) protein expression in lumbar dorsal root ganglia (DRGs). The molecular and cellular mechanisms underlying altered mechano- and metabo-sensitive afferent limb in CHF have not been fully understood. Our preliminary data showed that myocardial infarct (MI) triggered time-dependent macrophage infiltration into lumbar DRGs, suggesting that a neural inflammatory cascade occurs in muscle afferent ganglia post MI. We hypothesize that macrophage activation in lumbar DRGs plays a critical role in muscle afferent sensitization as well as the exaggerated EPR via regulating Kv channels and glutamatergic signaling in CHF. We also hypothesize that macrophage activation in lumbar DRGs also serves as an upstream mechanism to cause the TRPV1 channel dysfunction in muscle metabo-sensitive neurons in CHF. In Aim 1, we propose to determine the time-dependent macrophage infiltration/activation in lumbar (L4-L6) DRGs in post-MI male and female rats as well as post-MI CX3CR1CreER-tdTomato reporter mice. We will also plan to identify the pro-inflammatory (M1)/anti-inflammatory (M2) phenotypes of macrophages in lumbar DRGs post MI. Finally we will determine if pharmacological macrophage inhibition in lumbar DRGs can restore the exaggerated EPR as well as muscle afferent sensitization in CHF male and female rats. Aim 2 is designed to address how macrophages influence muscle afferent neuronal excitability post MI. We will determine if local pharmacological macrophage inhibition in lumbar DRGs can restore altered Kv channels, TRPV1 channel and glutamatergic dysfunction in CHF male and female rats. We will use highly integrative techniques including molecular (real-time PCR, western blot, immunofluorescence and tissue clearance), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test our hypotheses in this project. We believe that this proposed research will address important functional and mechanistic issues that directly relate to the quality of life in patients with CHF. These data will uncover new targets for therapy in this patient population.

慢性心力衰竭 (CHF) 是美国主要的死亡原因之一。该疾病是体力活动期间交感神经兴奋升高和运动不耐受。运动期间在心力衰竭患者经常会看到交感神经系统极度活跃，并引起心力衰竭。过度升压反应伴有过度换气。这些异常可能会增加这些患者体力活动期间的心血管风险。实验证据表明 1) 运动期间过度的交感神经兴奋与运动敏感性的增加直接相关升压反射（EPR）； 2）该反射的增强的机械敏感传入成分（即机械感受反射）主要导致 CHF 中 EPR 的过度增强，3）由以下因素激活的肌肉代谢反射：股动脉内注射辣椒素在 CHF 大鼠中减弱，这与下调腰背根神经节瞬时受体电位香草酸 1 型 (TRPV1) 蛋白表达（DRG）。改变机械和代谢敏感传入的分子和细胞机制 CHF 中的肢体尚未完全了解。我们的初步数据显示，心肌梗塞（MI）引发时间依赖性巨噬细胞浸润腰椎 DRG，表明神经炎症级联反应发生在 MI 后的肌肉传入神经节中。我们假设腰椎 DRG 中的巨噬细胞激活起着通过调节 Kv 通道和在肌肉传入敏化以及夸大 EPR 中发挥关键作用 CHF 中的谷氨酸信号传导。我们还假设腰椎 DRG 中的巨噬细胞激活也起到作为导致肌肉代谢敏感神经元 TRPV1 通道功能障碍的上游机制瑞士法郎。在目标 1 中，我们建议确定腰椎中时间依赖性巨噬细胞浸润/激活 (L4-L6) MI 后雄性和雌性大鼠以及 MI 后 CX3CR1CreER-tdTomato 报告小鼠的 DRG。我们将还计划鉴定腰椎巨噬细胞的促炎（M1）/抗炎（M2）表型 MI 后的 DRG。最后我们将确定腰椎 DRG 中的药理学巨噬细胞抑制是否可以恢复 CHF 雄性和雌性大鼠中过度的 EPR 以及肌肉传入敏化。目标2已设计解决巨噬细胞如何影响心肌梗死后肌肉传入神经元的兴奋性。我们将确定是否本地腰椎 DRG 中的药理学巨噬细胞抑制可以恢复改变的 Kv 通道、TRPV1 通道和 CHF 雄性和雌性大鼠的谷氨酸功能障碍。我们将使用高度集成的技术，包括分子（实时 PCR、蛋白质印迹、免疫荧光和组织清除）、细胞（膜片钳）和整个动物实验（测量 EPR 功能，单传入记录）来测试我们的假设项目。我们相信，这项拟议的研究将解决重要的功能和机械问题与CHF患者的生活质量直接相关。这些数据将揭示该领域的新治疗目标患者群体。