Sleep Apnea Links Obesity to Cardiovascular Dysfunction

描述(申请人提供)：肥胖症在美国正达到流行的程度，并与严重的心血管疾病和死亡率有关，是一个主要的公共卫生负担。超过50%的肥胖者出现睡眠呼吸暂停(SA)，其特征是睡眠时上呼吸道塌陷，导致反复的间歇性低氧(IH)和正常睡眠结构的碎片化。SA，尤其是IH的刺激，可以导致一系列信号通路的异常，从而导致心血管疾病。目前的提议集中在三个关键的信号通路-一氧化氮(NO)和瘦素。和肿瘤坏死因子a(TNFa)--这是SA和肥胖症的共同特征，可以影响心脏功能。这一建议的前提是SA的IH刺激引起心脏应激，导致心室肥厚和心肌收缩能力改变。SA和肥胖同时发生的NO和瘦素信号的缺失以及TNFa水平的升高将加剧心肌肥厚并减弱心肌收缩能力的代偿性增加。因此，总体假设是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一种机制。三个特定的目标检测NO和瘦素缺乏以及心脏TNFa水平过表达对IH五周心脏反应的影响。在特定的目标#1中，假设心肌收缩能力在神经元中的增加比内皮一氧化氮合酶亚型对IH的反应更大，而不同亚型之间的心肌肥厚程度是相同的。在特定的目的#2中，假设瘦素的缺乏会抑制心肌的收缩能力，并加重IH引起的心室肥厚程度。在特定的目的#3中，假设心肌收缩能力的降低和心肌肥厚的增加是通过心脏特异性的TNFa对IH的反应而发生的。我们的方法利用瘦基因敲除和转基因小鼠，以及使用药物干预的补充对照研究，独立于肥胖的混杂影响，检查在整个心脏水平和分离的心肌细胞对IH的反应中心脏功能的变化。这些拟议的研究将剖析SA加剧肥胖相关心血管疾病的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.