Novel mechanistic pathways of cardiovascular disease in obesity

 描述(申请人提供)：心血管疾病继发的发病率和死亡率是肥胖患者的主要健康问题。肥胖患者背负着一系列与超重相关的代谢功能障碍，这导致了这一人群明显的心血管疾病。虽然这种相关性已经确立，但可以用于治疗的机械性联系在很大程度上是缺乏的。在对这项提议的初步研究中，我们提出了两项主要意见，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时血管损伤的关键触发因素。通过删除限制胰岛素信号或肌肉生长的基因来纠正快速葡萄糖代谢，似乎可以在体外恢复内皮功能，并可能从系统上支持心血管缺陷。第二个观察结果是NADPH氧化酶1(Nox1)是肥胖患者血管缺陷的主要罪魁祸首。Nox1在肥胖小鼠的大小血管中过表达，似乎是由葡萄糖过高驱动的，可能是通过Galectin-3的上调。在目前的提案中，我们将从三个目标严格检验这些概念。First的目标是使用最先进的体外分子技术来确定血浆环境(特别是葡萄糖)变化导致NOx表达和超氧化物产生变化的信号机制，重点是Galectin-3的作用。第二个目标是在基因肥胖的背景下培育新的Nox1和Galectin-3 KO小鼠，以测试这两条氧化途径在体外导致血管功能障碍的假设，重点是确定通过增加肌肉质量来改善代谢是否排除了促氧化途径。第三个目标是在活体内追求这些概念，测试增加肌肉质量或阻断Nox1/Galectin-3信号轴是否可以改善心血管结果，如血压和血管对血流动力学应激的适应。综上所述，这些研究将为肥胖引起的代谢功能障碍的机制、介体和生理影响提供新的信息。成功完成这些目标可能会确定新的靶点，以帮助治疗肥胖症最紧迫的一些临床后果。

 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.