Novel mechanistic pathways of cardiovascular disease in obesity

 描述（由申请人提供）：继发于心血管疾病的发病率和死亡率是肥胖患者的主要健康问题。肥胖患者负担着一系列与超重相关的代谢功能障碍，这些代谢功能障碍导致该人群中明显的心血管疾病。虽然这种相关性是公认的，但在很大程度上缺乏可用于治疗的机制联系。在对这一建议的初步研究中，我们提出了两项重要意见，为这一问题提供了重要的新线索。首先，骨骼肌代谢控制的丧失似乎是肥胖症血管损伤的关键触发因素。通过删除限制胰岛素信号传导或肌肉生长的基因来纠正快速葡萄糖处置似乎可以恢复体外内皮功能，并可能支持全身性心血管缺陷。第二个观察结果是NADPH氧化酶1（Nox 1）是肥胖症血管缺陷的罪魁祸首。Nox 1在肥胖小鼠的大小血管中过表达，似乎是由葡萄糖过量驱动的，可能是通过半乳糖凝集素-3的上调。在本提案中，我们将在三个目标中严格测试这些概念。第一个目标将使用最先进的体外分子技术来确定信号传导机制，通过该机制，血浆环境的变化，特别是葡萄糖，诱导Nox表达和超氧化物产生的变化，特别强调半乳糖凝集素-3的作用。第二个目标是在遗传性肥胖背景下产生新的Nox 1和Galectin-3 KO小鼠，以测试这两种氧化剂途径导致体外血管功能障碍的假设，特别强调确定通过增加肌肉质量改善代谢是否会消除促氧化剂途径。第三个目标将在体内追求这些概念，测试增加肌肉质量或阻断Nox 1/Galectin-3信号传导轴是否会改善心血管结局，如血压和血管对血流动力学应激的适应。总之，这些研究将为肥胖引起的代谢功能障碍的机制、介质和生理影响提供新的信息。这些目标的成功完成可能会发现新的目标，以帮助治疗肥胖症的一些最紧迫的临床结果。

 DESCRIPTION (provided by applicant): Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight which drive the cardiovascular disease evident in this population. While this correlation is well-established, mechanistic links that could be exploited therapeutically are largely lacking. In preliminary studies for this proposal, we have made two major observations that shed significant new light on this issue. The first is that loss of metabolic control in skeletal muscle appears to be the key trigger for vascular injury in obesity. Correction of rapid glucose disposal by deletion of genes that limit insulin signaling or muscle growth appear to restore endothelial function in vitro and may underpin cardiovascular defects systemically. The second observation is the NADPH Oxidase 1 (Nox1) is a major culprit in vascular defects in obesity. Nox1 is overexpressed in large and small vessels from obese mice and appears driven by glucose excess, potentially via upregulation of galectin-3. In the current proposal, we will rigorously test these concepts in three aims. The firs aim will use state-of-the-art molecular techniques in vitro to determine the signaling mechanisms by which changes in the plasma milieu, specifically glucose, induce changes in Nox expression and superoxide production with specific emphasis on the role of galectin-3. The second aim will generate novel Nox1 and Galectin-3 KO mice on a genetically obese background to test the hypothesis that these two oxidant pathways contribute to vascular dysfunction in vitro with a specific emphasis on determining whether improving metabolism by increasing muscle mass obviates pro oxidant pathways. The third aim will pursue these concepts in vivo, testing whether increased muscle mass or blocking the Nox1/Galectin-3 signaling axis improves cardiovascular outcomes like blood pressure and vascular adaptions to hemodynamic stress. Taken together, these studies will provide new information on the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of some the most pressing clinical outcomes of obesity.