The role of serotonin in central sleep apnea, sympathoexcitation, and heart failure in spinalcord injured mice.

血清素在脊髓损伤小鼠中枢性睡眠呼吸暂停、交感神经兴奋和心力衰竭中的作用。

• 批准号: 10537827
• 负责人: QINGCHAO QIU
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537827
• 关键词: Affect; Age; Air Movements; Animals; Apnea; Arousal; Atrial Fibrillation; Biological Markers; Blood Pressure; Brain; Brain Stem; Breathing; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Central Nervous System; Central Sleep Apnea; Classification; Cognitive; Coronary Arteriosclerosis; Coupled; Development Plans; Disinhibition; EFRAC; Echocardiography; Event; Frequencies; Functional disorder; Galectin 3; General Population; Genes; Genetic; Geometry; Growth; Heart Atrium; Heart Rate; Heart failure; Hypercapnia; Hypertension; Hypertrophy; Hypoxia; Inflammatory; Interleukin-6; Knockout Mice; Knowledge; Lead; Left; Left Ventricular Ejection Fraction; Left Ventricular Hypertrophy; Left Ventricular Mass; Link; Mammals; Measures; Metabolic; Modality; Modification; Motor Neurons; Mus; Myocardial dysfunction; Natriuretic Peptides; Nerve; Neurologic; Neurons; Obstructive Sleep Apnea; Outcome; Oxidative Stress Induction; Pathologic; Patients; Peroxidases; Reflex action; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonergic System; Serotonin; Sleep; Sleep Apnea Syndromes; Spinal Cord; Spinal cord injury; Stroke; Sympathetic Nervous System; TNF gene; TPH2; Testing; Therapeutic; Time; Troponin; Ventricular; Veterans; Wild Type Mouse; Withdrawal; Work; circadian; comorbidity; connectin; diagnostic tool; heart function; improved; injured; military veteran; mortality; neural; protein biomarkers; receptor; respiratory; response; sensory feedback; treatment planning; Affect; Age; Air Movements; Animals; Apnea; Arousal; Atrial Fibrillation; Biological Markers; Blood Pressure; Brain; Brain Stem; Breathing; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Central Nervous System; Central Sleep Apnea; Classification; Cognitive; Coronary Arteriosclerosis; Coupled; Development Plans; Disinhibition; EFRAC; Echocardiography; Event; Frequencies; Functional disorder; Galectin 3; General Population; Genes; Genetic; Geometry; Growth; Heart Atrium; Heart Rate; Heart failure; Hypercapnia; Hypertension; Hypertrophy; Hypoxia; Inflammatory; Interleukin-6; Knockout Mice; Knowledge; Lead; Left; Left Ventricular Ejection Fraction; Left Ventricular Hypertrophy; Left Ventricular Mass; Link; Mammals; Measures; Metabolic; Modality; Modification; Motor Neurons; Mus; Myocardial dysfunction; Natriuretic Peptides; Nerve; Neurologic; Neurons; Obstructive Sleep Apnea; Outcome; Oxidative Stress Induction; Pathologic; Patients; Peroxidases; Reflex action; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonergic System; Serotonin; Sleep; Sleep Apnea Syndromes; Spinal Cord; Spinal cord injury; Stroke; Sympathetic Nervous System; TNF gene; TPH2; Testing; Therapeutic; Time; Troponin; Ventricular; Veterans; Wild Type Mouse; Withdrawal; Work; circadian; comorbidity; connectin; diagnostic tool; heart function; improved; injured; military veteran; mortality; neural; protein biomarkers; receptor; respiratory; response; sensory feedback; treatment planning

Project Summary Sleep apnea, which affects 2-4% of the general population and 8-10% in the veteran population, is 15 times more prevalent in patients with spinal cord injury (SCI). Sleep apnea is linked to cardiovascular co-morbidities, including hypertension, coronary artery disease (CAD), stroke, and atrial fibrillation, along with autonomic, metabolic, and cognitive co-morbidities. There are three neurally regulated mechanisms that determine the frequency and duration of apneic events: upper airway collapsibility and the arousal and chemoreflex response to hypoxia and hypercapnia. Our work revealed that the arousal and chemoreflex response to hypoxia and hypercapnia are blunted in mice with a deficiency of serotonin (5-HT) in the central nervous system (TPH2-/-). Additionally, we also uncovered that SCI leads to depletion of 5-HT in the central nervous system in wild-type mice (TPH2+/+), coupled to blunting of the arousal and chemoreflex response to hypoxia and hypercapnia. We hypothesize that blunting of the arousal and chemoreflex response to hypoxia and hypercapnia leads to increases in apnea frequency and duration. In addition to these modifications, we propose that the depletion of 5-HT in the central nervous system is accompanied by alterations in left ventricular geometry in TPH2-/- mice and increases in sympathetic nervous system activity (SNSA) that could lead to heart failure. Our preliminary work revealed left ventricular hypertrophy was evident in TPH2-/- mice, as evidenced by a conserved ejection fraction and an increase in left ventricular mass. Likewise, increased SNSA was evident in the TPH2-/- mice. We hypothesize that these changes observed in TPH2-/- mice will also be evident in TPH2+/+ mice following SCI. We propose that our results provide an underlying unifying mechanism that could explain the link between central sleep and heart failure in SCI mammals. The results will also provide the rationale to therapeutically modulates 5-HT levels and its receptor sub-types to mitigate centrally modulated apneic events and cardiac dysfunction in Veterans with intact or injured spinal cord.

项目摘要 睡眠呼吸暂停会影响一般人群的2-4％，在退伍军人人口中为8-10％ 在脊髓损伤患者（SCI）中更普遍。睡眠呼吸暂停与心血管合并症有关， 包括高血压，冠状动脉疾病（CAD），中风和心房颤动，以及自主神经 代谢和认知合并症。有三种神经调节的机制决定了 呼吸暂停事件的频率和持续时间：上气道可折叠性以及唤醒和化学反射响应 到缺氧和高碳酸血症。我们的工作表明，唤醒和化学反射反应对缺氧和 在中枢神经系统（TPH2 - / - ）中，高脑脂蛋白在患有5-羟色胺（5-HT）的小鼠中被钝化。 此外，我们还发现SCI导致野生型中枢神经系统中的5-HT耗竭 小鼠（TPH2+/+），与唤醒和化学反射反应对缺氧和高碳酸盐的反应相结合。我们 假设唤醒和化学反射反应对缺氧和高碳酸血症的反应导致 呼吸暂停频率和持续时间增加。除了这些修改之外，我们还建议 中枢神经系统中的5-HT伴随着TPH2 - / - 小鼠左心室几何形状的改变 并增加交感神经系统活动（SNSA），可能导致心力衰竭。我们的初步 工作表明，左心室肥大在TPH2 - / - 小鼠中很明显，这可以通过保守的射血 分数和左心室质量的增加。同样，在TPH2 - / - 小鼠中，SNSA增加也很明显。 我们假设在TPH2 - / - 小鼠中观察到的这些变化也将在TPH2+/+小鼠中很明显 科学。我们建议我们的结果提供了一种基本的统一机制，可以解释链接 在中心睡眠和科学哺乳动物的心力衰竭之间。结果还将为 在治疗上调节5-HT水平及其受体亚型以减轻中央调节的呼吸暂停事件 脊髓完整或受伤的退伍军人中的心脏功能障碍。