Intermittent hypoxia, adiponectin, and insulin resistance in cardiovascular risk

描述（由申请人提供）：周期性间歇性缺氧（IH）正在成为阻塞性睡眠呼吸暂停（OSA）患者胰岛素抵抗和心血管疾病发展的重要因素。阻塞性睡眠呼吸暂停在充血性心力衰竭（CHF）患者中非常常见，发生率高达三分之一。胰岛素抵抗也与心功能障碍的发展有关。持续气道正压通气（CPAP）治疗OSA可缓解睡眠时IH，提高胰岛素敏感性，改善心功能，提示IH是影响心肌功能的重要因素。IH导致胰岛素抵抗及相关心血管疾病和心肌功能障碍的机制尚不清楚。脂肪组织合成并分泌多种生物活性肽，统称为“脂肪细胞因子”。脂联素（Ad）是一种仅在白色脂肪组织中合成的脂肪细胞因子，近年来由于其强大的生理作用和多效性作用，包括抗糖尿病、抗动脉粥样硬化和抗炎作用，受到了相当大的关注。胰岛素抵抗个体的总循环Ad水平较低。环状IH（与人类OSA相关的IH相似）是否会降低脂肪细胞中的Ad表达和分泌尚不清楚。因此，在Specific Aim 1中，我们将研究IH是否会改变脂肪细胞中的Ad分泌，从而增加这些细胞的胰岛素抵抗。Ad可防止心肌梗死后收缩功能障碍的发生。Ad缺乏可导致压力过载状态下进行性心脏重构，并可防止培养心肌细胞的细胞肥大。目前尚不清楚IH诱导的胰岛素抵抗是否会导致心肌功能障碍。因此，在Specific Aim 2中，我们将在动物模型中建立脂联素在体内间歇性缺氧诱导的胰岛素抵抗和相关心肌功能障碍的调节中发挥重要作用。由于胰岛素抵抗是左心室收缩和舒张功能的危险因素，而且我们的初步数据显示，OSA患者的IH治疗增加了Ad的生物活性高分子量形式，因此本提议的Specific Aim 3将涉及转化研究，以检查CPAP治疗OSA和心力衰竭患者对胰岛素抵抗和Ad水平的影响。并通过心脏磁共振成像将这些变化与心脏结构和功能的变化联系起来。为了实施这一建议，我们组建了一个由临床医生、基础科学家和Ad生物学权威人士组成的团队。这些临床科学家和基础科学家之间的合作努力，在俄亥俄州立大学医学院多萝西·m·戴维斯心肺研究所的支持环境中，使我们能够从细胞和动物模型到人类受试者进行这些实验。

DESCRIPTION (provided by applicant): Cyclic intermittent hypoxia (IH) is emerging as an important factor in the development of insulin resistance and cardiovascular diseases in patients with obstructive sleep apnea (OSA). OSA is very common in congestive heart failure (CHF) occurring in up to a third of patients. Insulin resistance has also been linked to the development of cardiac dysfunction. Treatment of OSA with continuous positive airway pressure (CPAP) alleviates the IH during sleep, increases insulin sensitivity, as well as improves cardiac function, suggesting that IH is a crucial factor affecting myocardial function. The mechanisms by which IH is responsible for insulin resistance and associated cardiovascular diseases and myocardial dysfunctions are unclear. Adipose tissue synthesizes and secretes a wide variety of bioactive peptides which are collectively called "adipocytokines". Adiponectin (Ad), an adipoctyokine that is exclusively synthesized in white adipose tissue, has received considerable attention in recent years because of its potent physiological effects and pleiotropic actions which include its antidiabetic, antiatherogenic, and anti-inflammatory effects. Total circulating Ad levels have been shown to be lower in insulin-resistant individuals. Whether cyclic IH (similar to that encountered during the IH associated with OSA in humans) decreases Ad expression and secretion in adipocytes is not known. Therefore, in Specific Aim 1, we will examine whether IH alters Ad secretion in adipocytes resulting in increased insulin resistance in these cells. Ad protects against the development of systolic dysfunction following myocardial infarction. Ad deficiency leads to progressive cardiac remodeling in pressure overloaded condition and it also prevents cellular hypertrophy in cultured myocytes. It is not known whether the insulin resistance induced by IH contributes to myocardial dysfunction. Therefore, in Specific Aim 2, we will establish that adiponectin plays an important role in the modulation of insulin resistance and associated myocardial dysfunction induced by intermittent hypoxia in vivo, in animal models. Since insulin resistance is a risk factor for left ventricular systolic and diastolic function, and also our preliminary data show that treatment of IH in OSA increases the biologically active high-molecular-weight form of Ad, Specific Aim 3 of this proposal will involve translational research to examine the effects of CPAP treatment in human patients with OSA and heart failure, on insulin resistance and Ad levels, and associate these with changes in cardiac structure and function using cardiac magnetic resonance imaging. To carry out this proposal, we have assembled a team consisting of clinicians, basic scientist, and a leading authority on Ad biology. These collaborative efforts among clinician scientists and basic scientists, in a supportive environment at the Dorothy M. Davis Heart & Lung Institute of the Ohio State University College of Medicine, allow us to perform these experiments from cells and animal models to human subjects. PUBLIC HEALTH RELEVANCE: Intermittent hypoxia associated with obstructive sleep apnea is a very common problem that is an important risk factor for cardiovascular disease. Knowledge of the mechanisms of how adiponectin protects against intermittent hypoxia-induced insulin resistance and associated myocardial dysfunction, may provide novel treatment strategies for patients with sleep apnea and cardiovascular disease.