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

• 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
• 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

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。 这种疾病是在体力活动中交感神经兴奋和运动耐受性增加。在锻炼期间 心力衰竭患者，交感神经系统的极度激活是常见的，并引起 伴有过度换气的过度升压反应。这些异常现象可能会增加 这些患者在体力活动期间的心血管风险。实验证据表明：1) 运动中过度的交感神经兴奋与运动的敏感性增加直接相关。 加压反射(EPR)；2)该反射的机械敏感的增强传入成分(即 机械反射)主要导致CHF中EPR的夸大，3)肌肉代谢反射被激活 CHF大鼠股动脉注射辣椒素被钝化，这与表达下调有关 腰椎背根神经节中TRPV1蛋白的表达 (DRGs)。机械和代谢敏感传入改变的分子和细胞机制 肢体在充血性心力衰竭中的作用尚不完全清楚。我们的初步数据显示，心肌梗死(MI)引发 腰椎背根神经节内的时间依赖性巨噬细胞浸润，提示神经炎性级联反应 发生在心肌梗塞后的肌肉传入神经节。我们假设腰椎背根神经节中巨噬细胞的激活在 在肌肉传入敏化中的关键作用以及通过调节Kv通道和 充血性心力衰竭中的谷氨酸能信号转导。我们还假设腰椎背根神经节中巨噬细胞的激活也有助于 作为导致骨骼肌代谢敏感神经元TRPV1通道功能障碍的上游机制 瑞士法郎。在目标1中，我们建议测定腰椎巨噬细胞的时间依赖性的渗透/激活。 (L4-L6)心肌梗死后雄性和雌性大鼠以及心肌梗死后CX3CR1Creer-tdTomato报告小鼠的DRGs。我们会 还计划确定腰椎巨噬细胞的促炎(M1)/抗炎(M2)表型 心肌梗死后出现DRG。最后，我们将确定药物抑制腰椎背根神经节中的巨噬细胞是否可以恢复 CHF雌雄大鼠EPR的夸大及肌肉传入敏化。AIM 2是专门设计的 探讨巨噬细胞如何影响心肌梗死后肌肉传入神经元的兴奋性。我们将确定当地是否 药理抑制腰背根节巨噬细胞可恢复改变的Kv通道、TRPV1通道和 CHF雄性和雌性大鼠的谷氨酸能功能障碍。我们将使用高度集成的技术，包括 分子(实时聚合酶链式反应、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，单一传入记录)来验证我们的假设 项目。我们相信，这项拟议的研究将解决重要的功能和机制问题， 直接关系到充血性心力衰竭患者的生活质量。这些数据将揭示治疗的新靶点。 病人群体。