Sleep Apnea Links Obesity to Cardiovascular Dysfunction

描述（由申请人提供）：肥胖在美国已达到流行病的程度，并与显著的心血管发病率和死亡率相关，是一个主要的公共卫生负担。超过50%的肥胖者表现为睡眠呼吸暂停（SA），其特征是睡眠时上呼吸道塌陷，导致反复的间歇性缺氧（IH）和正常睡眠结构的破碎。SA，特别是IH的刺激，可导致一系列导致心血管疾病的信号通路异常。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) - SA和肥胖都常见，并能影响心功能。该建议的前提是SA的IH刺激引起心脏应激，导致心室肥厚和心脏收缩力改变。一氧化氮和瘦素信号的缺陷以及tnf水平的升高都发生在SA和肥胖中，这将加剧肥厚并减弱心脏收缩力的代偿性增加。因此，总的假设是SA是肥胖和心血管疾病之间的联系，而NO、瘦素和TNFa信号的缺陷为这种联系提供了机制。Three Specific Aims研究NO和瘦素缺乏以及心脏TNFa水平过表达对5周IH心脏反应的影响。在Specific Aim #1中。假设在IH的反应中，神经元型的心肌收缩力比内皮型的心肌收缩力增加更多，而心室肥大的程度在同种异构体之间是相同的。在特定目标#2中。据推测，瘦素的缺失会抑制心脏收缩力，加重IH引起的心室肥厚程度。在Specific Aim #3中。据推测，心脏收缩力的下降和心室肥厚的增加是通过对IH的反应中TNFa的心脏特异性作用发生的。我们的方法利用瘦基因敲除和转基因小鼠以及使用药理学干预的补充对照研究来检查，独立于肥胖的混杂效应，在整个心脏和分离的心肌细胞水平上发生的心脏功能变化对IH的反应。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。

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.