Intermittent hypoxia, adiponectin, and insulin resistance in cardiovascular risk

间歇性缺氧、脂联素和胰岛素抵抗与心血管风险的关系

• 批准号: 7782902
• 负责人: ULYSSES J MAGALANG
• 金额: $ 38.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-04 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782902
• 关键词: Adipocytes; Adipose tissue; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antidiabetic Drugs; Attention; Biology; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cells; Congestive Heart Failure; Continuous Positive Airway Pressure; Coupled; Data; Development; Endocrine Glands; Environment; Exposure to; Functional disorder; Heart; Heart failure; Human; Hypertrophy; Hypoxia; Individual; Institutes; Insulin Resistance; Knowledge; Left; Link; Lung; Magnetic Resonance Imaging; Medicine; Modeling; Molecular Weight; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial dysfunction; Obesity; Obstructive Sleep Apnea; Ohio; Patients; Peptides; Physiological; Physiological Processes; Play; Proteins; Regulation; Risk; Risk Factors; Role; Scientist; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Stimulus; Structure; System; Time; Transgenic Organisms; Translational Research; Universities; Ventricular; adiponectin; airway obstruction; attenuation; authority; cardiovascular risk factor; college; glucose transport; human subject; improved; in vivo; insulin sensitivity; mouse model; novel; overexpression; pressure; prevent; public health relevance; research study; treatment strategy

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.

描述（由申请人提供）：在阻塞性睡眠呼吸暂停患者（OSA）患者中，环状间歇性缺氧（IH）成为发展胰岛素抵抗和心血管疾病的重要因素。 OSA在多达三分之一的患者中发生的充血性心力衰竭（CHF）非常普遍。胰岛素抵抗也与心脏功能障碍的发展有关。连续阳性气道压力（CPAP）对OSA进行处理可减轻睡眠期间的IH，提高胰岛素敏感性并改善心脏功能，这表明IH是影响心肌功能的关键因素。 IH负责胰岛素抵抗和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，这些肽统称为“脂肪细胞因子”。脂联素（AD）是一种仅在白脂肪组织中合成的脂肪肌动物，近年来由于其有效的生理作用和多效性作用而受到了相当大的关注，其中包括其抗糖尿病，抗动脉粥样硬化和抗炎作用。在胰岛素耐药的个体中，总循环AD水平已显示出较低的水平。是否尚不清楚循环IH（类似于与人类在人类中相关的IH中遇到的与OSA相关的IH）是否降低脂肪细胞中的AD表达和分泌。因此，在特定的目标1中，我们将检查IH是否改变了脂肪细胞中的AD分泌，从而导致这些细胞中胰岛素抵抗的增加。 AD可以防止心肌梗塞后收缩功能障碍的发展。 AD缺乏会导致在压力过载条件下进行性心脏重塑，并且还可以防止培养的肌细胞中的细胞肥大。尚不清楚IH引起的胰岛素抵抗是否导致心肌功能障碍。因此，在特定目标2中，我们将确定脂联素在动物模型中间歇性缺氧引起的胰岛素抵抗和相关的心肌功能障碍的调节中起重要作用。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表明，OSA中IH的治疗增加了AD的生物活性高分子量的形式，该提案的特定目的3将涉及翻译研究，以检查使用cpap cpap的cpap患者的cpap和心脏失败的影响，并关联了对媒体和心脏失效的效果，并将其与胰岛素抗性，以及胰岛素抑制作用相关，并且共振成像。为了提出这项建议，我们组建了一个由临床医生，基础科学家和广告生物学领先的机构组成的团队。在俄亥俄州立大学医学院多萝西·戴维斯心脏和肺研究所的支持环境中，临床科学家和基础科学家之间的这些合作努力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。 公共卫生相关性：与阻塞性睡眠呼吸暂停相关的间歇性缺氧是一个非常普遍的问题，是心血管疾病的重要危险因素。了解脂联素如何预防间歇性缺氧诱导的胰岛素抵抗和相关心肌功能障碍的机制可能会为患有睡眠呼吸暂停和心血管疾病的患者提供新颖的治疗策略。