Exercise Pressor Reflex Dysfunction in Heart Failure: Mechanisms and Treatment

心力衰竭的运动加压反射功能障碍：机制和治疗

• 批准号: 10222760
• 负责人: Steven W Copp
• 金额: $ 29.84万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222760
• 关键词: Activities of Daily Living; Afferent Neurons; Animals; Autonomic nervous system; Biological Models; Blood Pressure; Cardiovascular system; Caring; Contracts; Dinoprostone; EP4 receptor; Exercise; Exercise Tolerance; Exhibits; Female; Functional disorder; Grant; Health Care Costs; Heart; Heart Rate; Heart failure; Hindlimb; Individual; Mechanics; Mechanoreceptors; Medical; Messenger RNA; Metabolic; MicroRNAs; Modeling; Molecular; Muscle; Muscle Contraction; Myocardial; Myocardial Infarction; Myocardial Ischemia; Nerve; Operative Surgical Procedures; Opioid Receptor; Oxygen; PTGS2 gene; Patient risk; Patients; Performance; Peripheral; Pharmacology; Piezo 2 ion channel; Play; Prostaglandin Receptor; Prostaglandins; Proteins; Quality of life; Rat-1; Rattus; Reflex action; Rest; Risk; Role; Sensory; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Stretching; Sympathetic Nervous System; Techniques; Testing; Thinness; Tissues; United States; Woman; arm; base; coronary vasoconstriction; cyclooxygenase 2; exercise capacity; exercise intolerance; experimental study; functional independence; in vivo; interstitial; knock-down; mRNA Expression; male; men; mu opioid receptors; receptor; relating to nervous system; therapeutic target; therapy design

PROJECT SUMMARY There are currently ~6.5 million men and women in the United States with heart failure. By 2030, that number is predicted to climb to over 8.5 million and direct heart failure-related health care costs are predicted to command $53.1 billion. Heart failure patients commonly exhibit exaggerated levels of sympathetic nervous system activity at rest and during exercise compared to healthy subjects. An exaggerated increase in sympathetic nervous system activity during exercise (i.e., sympatho-excitation) is a direct contributor to exercise intolerance and lack of functional independence which is the main reason that heart failure patients seek medical care. A neural reflex that is activated by mechanical and metabolic signals within contracting skeletal muscles contributes importantly to the increase in sympathetic nervous system activity that occurs during exercise. In heart failure patients, the activation of this reflex, termed the exercise pressor reflex, is exaggerated which underlies mechanistically the exercise-induced sympatho-excitation. Currently, there are no therapies that are designed specifically to reduce the activation of the exercise pressor reflex in heart failure patients which reflects our current limited understanding of the mechanisms that contribute to its exaggeration. We will use male and female rats with surgically-induced heart failure (post-myocardial infarction model) to study the mechanistic bases and possible therapeutic targets of the exaggerated exercise pressor reflex. In Aim 1, we will investigate the role played by endoperoxide (EP) 4 receptors, which are stimulated by prostaglandins produced within skeletal muscles, in evoking the exercise pressor reflex in heart failure. In Aim 2, we will investigate the role played by mechanically activated piezo2 channels in evoking the exercise pressor reflex in heart failure. In Aim 3, we will investigate whether peripheral δ-opioid receptor stimulation reduces the exercise pressor reflex in heart failure. We will investigate these aims using a complementary blend of whole animal and molecular level approaches so that our findings are integrative and translational. Collectively, our experiments may identity three possible targets (EP4 receptors, piezo2 channels, and δ-opioid receptors) for therapies aimed at 1) mitigating the sympatho-excitation that occurs during exercise and 2) increasing exercise tolerance, functional independence, and overall quality of life in heart failure patients.

项目概要 到 2030 年，美国目前约有 650 万名男性和女性患有心力衰竭。 预计这一数字将攀升至 850 万以上，并且与心力衰竭相关的直接医疗费用预计将增加 心力衰竭患者通常表现出过度的交感神经水平。 与健康受试者相比，休息时和运动时的系统活动过度增加。 运动期间的交感神经系统活动（即交感神经兴奋）是运动的直接贡献者 不耐受和缺乏功能独立性是心力衰竭患者寻求医疗的主要原因 由收缩骨骼肌内的机械和代谢信号激活的神经反射。 显着促进运动过程中交感神经系统活动的增加。 在心力衰竭患者中，这种反射（称为运动升压反射）的激活被夸大， 是运动引起的交感神经兴奋的机械基础，目前尚无治疗方法。 专门设计用于减少心力衰竭患者运动升压反射的激活，这反映了 我们目前对导致其夸大的机制的了解有限，我们将使用男性和男性。 手术诱发心力衰竭的雌性大鼠（心肌梗死后模型）研究其机制 在目标 1 中，我们将研究过度运动升压反射的基础和可能的治疗目标。 内过氧化物 (EP) 4 受体所发挥的作用，该受体受到体内产生的前列腺素的刺激 骨骼肌在诱发心力衰竭运动升压反射方面的作用，在目标 2 中，我们将研究其作用。 In Aim 中，机械激活的压电通道可激发运动升压反射。 3、我们将研究外周δ-阿片受体刺激是否会降低心脏的运动升压反射 我们将使用整个动物和分子水平的互补组合来研究这些目标。 总的来说，我们的实验可以确定三个。 治疗的可能靶点（EP4 受体、piezo2 通道和 δ-阿片受体）旨在 1) 缓解 运动过程中发生的交感神经兴奋，2) 增加运动耐量、功能性 心力衰竭患者的独立性和总体生活质量。

项目成果

Bradykinin 2 receptors contribute to the exaggerated exercise pressor reflex in a rat model of simulated peripheral artery disease.

在模拟外周动脉疾病的大鼠模型中，缓激肽 2 受体会导致运动升压反射过度。

• DOI: 10.1152/ajpregu.00274.2022
• 发表时间: 2023
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Butenas,AlecLE;Rollins,KorynneS;Williams,AuniC;Copp,StevenW
• 通讯作者: Copp,StevenW

Thromboxane A2 receptors mediate chronic mechanoreflex sensitization in a rat model of simulated peripheral artery disease.

在模拟外周动脉疾病的大鼠模型中，血栓素 A2 受体介导慢性机械感受反射敏化。

• DOI: 10.1152/ajpheart.00255.2020
• 发表时间: 2020
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Rollins,KorynneS;Butenas,AlecLE;Felice,KennedyP;Matney,JacobE;Williams,AuniC;Kleweno,TalynE;Copp,StevenW
• 通讯作者: Copp,StevenW

Protein Kinase C Epsilon Contributes to the Exaggerated Mechanoreflex in Rats with Heart Failure.

蛋白激酶 C Epsilon 导致心力衰竭大鼠的机械感觉反射过度。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Butenas,AlecLE;Parr,ShannonK;Hammond,StephenT;Ade,CarlJ;Hageman,KS;Musch,TimothyI;Copp,StevenW
• 通讯作者: Copp,StevenW

Cyclooxygenase inhibition does not impact the pressor response during static or dynamic mechanoreflex activation in healthy decerebrate rats.

环加氧酶抑制不会影响健康去大脑大鼠静态或动态机械感受反射激活期间的升压反应。

• DOI: 10.1152/ajpregu.00080.2019
• 发表时间: 2019
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Rollins,KorynneS;Hopkins,TylerD;Butenas,AlecL;Felice,KennedyP;Ade,CarlJ;Copp,StevenW
• 通讯作者: Copp,StevenW

GsMTx4 reduces the reflex pressor response during dynamic hindlimb skeletal muscle stretch in decerebrate rats.

GsMTx4 降低去大脑大鼠动态后肢骨骼肌拉伸过程中的反射性加压反应。

• DOI: 10.14814/phy2.13974
• 发表时间: 2019
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Sanderson,BaileyC;Rollins,KorynneS;Hopkins,TylerD;Butenas,AlecL;Felice,KennedyP;Ade,CarlJ;Copp,StevenW
• 通讯作者: Copp,StevenW