Sleep Apnea Links Obesity to Cardiovascular Dysfunction

睡眠呼吸暂停将肥胖与心血管功能障碍联系起来

• 批准号: 7093956
• 负责人: CHRISTOPHER P O'DONNELL
• 金额: $ 39.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093956
• 关键词: biological signal transduction; blood pressure; cardiovascular disorder risk; comorbidity; diagnostic catheterization; echocardiography; gender difference; gene induction /repression; genetic regulation; genetically modified animals; heart contraction; heart rate; hypoxia; laboratory mouse; leptin; muscle cells; nitric oxide; nitric oxide synthase; obesity; protein isoforms; sleep apnea; tissue /cell culture; tumor necrosis factor alpha; ventricular hypertrophy

DESCRIPTION (provided by applicant): Obesity is reaching epidemic proportions in the United States, and is associated with significant cardiovascular morbidity and mortality, representing a major public health burden. More than 50% of obese people exhibit Sleep Apnea (SA), which is characterized by upper airway collapse during sleep leading to repetitive periods of Intermittent Hypoxia (IH) and fragmentation of normal sleep architecture. SA, and in particular the stimulus of IH, can lead to a range of abnormalities in signaling pathways that cause cardiovascular disease. The current proposal focuses on three key signaling pathways - nitric oxide (NO), leptin. and tumor necrosis factor a (TNFa) - that are common to both SA and obesity and can impact on cardiac function. The premise of the proposal is that the IH stimulus of SA causes cardiac stress resulting in the development of ventricular hypertrophy and altered cardiac contractility. Deficits in NO and leptin signaling and increased levels of TNFa that occur with both SA and obesity will act to exacerbate the hypertrophy and attenuate the compensatory increases in cardiac contractility. Thus, the overall hypothesis is that SA is a link between obesity and cardiovascular disease, and that defects in NO, leptin, and TNFa signaling provide a mechanism for such a link. Three Specific Aims examine the effect of NO and leptin deficiency, and overexpression of cardiac TNFa levels on the cardiac responses to five weeks of IH. In Specific Aim #1. it is hypothesized that cardiac contractility increases more in neuronal than the endothelial NOS isoforms in response to IH, whereas the degree of ventricular hypertrophy is the same between isoforms. In Specific Aim #2. it is hypothesized that the absence of leptin will depress cardiac contractility and accentuate the degree of ventricular hypertrophy caused by IH. In Specific Aim #3. it is hypothesized that a decrease in cardiac contractility and an increase in ventricular hypertrophy occurs through a cardiac specific effect of TNFa in response to IH. Our approach utilizes lean knockout and transgenic mice and complementary control studies using pharmacological interventions to examine, independent of the confounding effects of obesity, the changes in cardiac function that occur both at the level of the whole heart and the isolated myocyte in response to IH. These proposed studies will dissect mechanisms by which SA exacerbates morbidity and mortality in obesity-related cardiovascular disease.

描述（由申请人提供）：肥胖在美国正达到流行病的比例，并与显著的心血管发病率和死亡率相关，代表了主要的公共卫生负担。超过50%的肥胖者表现出睡眠呼吸暂停（SA），其特征在于睡眠期间的上气道塌陷，导致反复的间歇性缺氧（IH）和正常睡眠结构的片段化。SA，特别是IH的刺激，可导致导致心血管疾病的信号通路的一系列异常。目前的建议集中在三个关键的信号通路-一氧化氮（NO），瘦素。和肿瘤坏死因子a（TNFa）-这是SA和肥胖症共同的，并且可以影响心脏功能。该提议的前提是SA的IH刺激引起心脏应激，导致心室肥大和心脏收缩力改变的发展。在SA和肥胖症中发生的NO和瘦素信号传导的缺陷和TNFa水平的增加将起到加剧肥大和减弱心脏收缩力的代偿性增加的作用。因此，总的假设是SA是肥胖和心血管疾病之间的联系，并且NO、瘦素和TNF α信号传导的缺陷提供了这种联系的机制。三个特定目的检查NO和瘦素缺乏以及心脏TNF α水平过表达对5周IH心脏反应的影响。具体目标#1假设响应IH，神经元NOS同工型的心肌收缩力比内皮NOS同工型的心肌收缩力增加更多，而心室肥大的程度在同工型之间相同。具体目标#2假设缺乏瘦素会抑制心肌收缩力并加重IH引起的心室肥大的程度。具体目标#3假设心肌收缩力的降低和心室肥大的增加是通过响应IH的TNF α的心脏特异性作用而发生的。我们的方法利用瘦基因敲除和转基因小鼠和补充对照研究，使用药物干预检查，独立的肥胖的混杂效应，心脏功能的变化，发生在整个心脏和孤立的心肌细胞的水平响应IH。这些拟议的研究将剖析SA加剧肥胖相关心血管疾病发病率和死亡率的机制。