Mechanisms of Vascular Dysfunction in Diet-Induced Obesity

说明(申请人提供)：肥胖和肥胖相关的危险因素与心血管疾病和包括颈动脉疾病和中风在内的事件的风险增加有关。人类最常见的肥胖类型是由饮食引起的肥胖。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。虽然肥胖症在美国的发病率正在增加，但关于肥胖症对血管系统的影响知之甚少，关于限制或促成氧化应激或血管内皮细胞功能障碍的机制更是知之甚少。因此，这项建议的总体目标是在一个由高脂肪饮食产生的饮食诱导肥胖模型中检查导致氧化应激和内皮功能障碍的潜在机制，该模型概括了人类肥胖的发展过程。首先，有人建议研究NAD(P)H氧化酶作为超氧化物的重要来源的潜在作用，超氧化物有助于高脂饮食所产生的血管功能障碍。其次，有人建议进行研究，以确定IL-6，一种强有力的促炎细胞因子，是否会导致高脂肪饮食所产生的氧化应激和血管功能障碍。研究旨在检查肥胖引起的IL-6增加是否与NA(D)PH氧化酶表达和/或活性增强有关。相反，有人提出研究，以确定IL-10，一种强大的抗炎细胞因子，是否限制氧化应激和血管功能障碍，以应对高脂肪饮食。研究旨在检验IL-10在限制肥胖的氧化应激和内皮功能障碍方面的保护作用是否通过调节NAD(P)H氧化酶活性和/或IL-6的减少来实现。第三，有人建议研究PARP-1的缺乏是否通过减少NAD(P)H氧化酶或IL-6的表达和/或增加IL-10或内皮一氧化氮合酶来限制氧化应激和内皮功能障碍的增加。PARP-1是氧化应激的下游靶标。我们的初步数据支持这些假设。检查导致或限制肥胖患者内皮功能障碍的机制很重要，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。这项研究的结果将为饮食诱导肥胖引起的氧化应激和内皮功能障碍的相关机制提供新的见解。 公共卫生相关性：肥胖与心血管疾病和包括颈动脉疾病和中风在内的事件的发生率增加有关。这项研究旨在研究NAD(P)H氧化酶、白介素6、白介素10和多聚(ADP)核糖聚合酶在饮食诱导肥胖的氧化应激和血管功能障碍中的作用。这些研究的结果应该为氧化应激和血管功能障碍的机制提供新的见解，以应对高脂肪饮食，并旨在改善公众健康。

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. PUBLIC HEALTH RELEVANCE: Obesity is associated with an increased incidence of cardiovascular disease and events including carotid artery disease and stroke. Studies in this proposal are designed to examine the role of NAD(P)H oxidase, interleukin-6, interleukin-10, and poly(ADP)- ribose polymerase in contributing to oxidative stress and vascular dysfunction in diet- induced obesity. Results from these studies should provide new insight into mechanisms related to oxidative stress and vascular dysfunction in response to a diet high in fat and are aimed at improving public health.