Mechanisms of Vascular Dysfunction in Diet-Induced Obesity

描述（由申请人提供）：肥胖和肥胖相关风险因素与心血管疾病和事件（包括颈动脉疾病和卒中）风险增加相关。人类最常见的肥胖类型是饮食诱导的肥胖。不适当的食物摄入，特别是高脂肪饮食，是人类饮食诱导肥胖的主要原因。虽然肥胖症的发病率在美国正在增加，但关于肥胖症对血管系统的影响知之甚少，关于限制或促成血管中的氧化应激或内皮功能障碍的机制更是知之甚少。因此，本提案的总体目标是研究在由高脂肪饮食产生的饮食诱导的肥胖模型中导致氧化应激和内皮功能障碍的潜在机制，以及重现人类肥胖发展的机制。首先，提出研究以检查NAD（P）H氧化酶作为导致高脂肪饮食产生的血管功能障碍的超氧化物的重要来源的潜在作用。第二，研究提出，以确定是否IL-6，一种有效的促炎细胞因子，有助于氧化应激和血管功能障碍产生的高脂肪饮食。设计研究以检查肥胖症发生的IL-6增加是否与增强的NA（D）PH氧化酶表达和/或活性相关。相反，研究提出，以确定是否IL-10，一种有效的抗炎细胞因子，限制氧化应激和血管功能障碍，以响应高脂肪饮食。设计研究以检查IL-10在限制肥胖症中的氧化应激和内皮功能障碍中的保护作用是否介导NAD（P）H氧化酶活性的降低和/或IL-6的降低。第三，提出研究以检查PARP-1（氧化应激的下游靶标）的缺乏是否通过NAD（P）H氧化酶或IL-6表达的减少和/或IL-10或内皮一氧化氮合酶的增加来限制响应于高脂肪饮食的氧化应激和内皮功能障碍的增加。我们的初步数据支持这些假设。研究导致或限制肥胖患者内皮功能障碍的机制非常重要，因为内皮功能障碍已成为未来心血管疾病和事件的独立临床预测因子。从拟议的研究中得出的结果应该提供新的洞察机制相关的氧化应激和内皮功能障碍，以应对饮食诱导的肥胖。

DESCRIPTION (provided by applicant): Obesity and obesity-related risk factors are associated with an increased risk of cardiovascular disease and events including carotid artery disease and stroke. The most common type of obesity in humans is diet-induced obesity. Inappropriate food-intake, particularly of a diet high in fat, is the primary cause of diet-induced obesity in humans. Although the incidence of obesity is increasing in the United States, very little is known regarding the effects of obesity on the vasculature and even less is known regarding mechanisms that limit or contribute to oxidative stress or endothelial dysfunction in blood vessels. Thus, the overall goal of this proposal is to examine potential mechanisms that contribute to oxidative stress and endothelial-dysfunction in a model of diet-induced obesity produced by a diet high in fat and one that recapitulates the development of obesity in humans. First, studies are proposed to examine the potential role of NAD(P)H oxidase as an important source of superoxide that contributes to vascular dysfunction produced by a high fat diet. Second, studies are proposed to determine whether IL-6, a potent pro-inflammatory cytokine, contributes to oxidative stress and vascular dysfunction produced by a high fat diet. Studies are designed to examine whether increases in IL-6 that occur with obesity are linked to enhanced NA(D)PH oxidase expression and/or activity. Conversely, studies are proposed to determine whether IL-10, a potent anti-inflammatory cytokine, limits oxidative stress and vascular dysfunction in response to a high fat diet. Studies are designed to examine whether the protective effect of IL-10 in limiting oxidative stress and endothelial dysfunction in obesity is mediated reductions in NAD(P)H oxidase activity and/or reduction in IL-6. Third, studies are proposed to examine whether deficiency of PARP-1, a downstream target of oxidative stress, limits the increase in oxidative stress and endothelial dysfunction in response to a high fat diet via reductions in NAD(P)H oxidase or IL-6 expression and/or increases in IL-10 or endothelial nitric oxide synthase. Our preliminary data support these hypotheses. Examination of mechanisms that contribute to or limit endothelial dysfunction in obesity are important because endothelial dysfunction has emerged as an independent clinical predictor of future cardiovascular disease and events. The results derived from the proposed studies should provide novel insight into mechanisms related to oxidative stress and endothelial dysfunction in response to diet-induced obesity.