Adipose autotaxin: a novel link between obesity and cardiovascular disease

描述(由申请人提供)： 在美国，肥胖和肥胖相关的心血管并发症是一个日益沉重的健康负担。一项对2000年在退伍军人医疗中心接受护理的近200万退伍军人的分析表明，~68%的退伍军人超重，~37%的退伍军人肥胖。与肥胖相关的医疗费用给退伍军人管理局的医疗保健系统带来了压力。肥胖是心血管疾病(CVD)和中风的既定危险因素，肥胖的心血管并发症是退伍军人潜在的可预防死亡的主要原因。除了传统的心血管疾病危险因素外，肥胖的特征还包括慢性亚急性炎症状态，巨噬细胞在脂肪中渗透，脂肪组织产生炎症介质。发炎的脂肪组织可能是促进动脉粥样硬化发展的全身性炎症介质的唯一因素。更好地了解脂肪组织在产生炎症介质中的作用最终将导致确定预防和治疗相关心血管疾病的新策略。最近的证据和我们自己的发现表明，脂肪组织对全身分泌的溶血磷脂酶D自体趋化蛋白(ATX)水平有贡献。ATX负责产生细胞外具有生物活性的溶血磷脂酸(LPA)，这是一种存在于血浆和其他生物液中生理相关水平的生物活性脂质，对人类健康和疾病发挥作用。基于ATX的表达随着肥胖的增加而增加的观察结果，以及ATX和LPA对单核细胞迁移和内皮通透性的影响，我们提出了ATX调控的信号通路参与肥胖相关炎症和动脉粥样硬化发展的中心假说。我们将使用最先进的遗传学和药理学方法在两个特定的目标上测试我们的中心假设。在第一个目标中，我们将确定脂肪来源的ATX在局部和全身炎症中的作用。在第二个目标中，我们将确定脂肪来源的ATX在动脉粥样硬化发展中的作用。这项资助的目的是提供一种工具来解决溶脂信号传递领域中一个尚未解决的主要问题，即脂肪衍生ATX在LPA介导的生物信号传递中的作用及其在动脉粥样硬化中的作用。这些结果将是重要的，因为它们有望提供创新的靶点，并为可用于预防和治疗人类肥胖的心血管并发症的新型抑制剂提供概念验证。

DESCRIPTION (provided by applicant): Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke, and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors, obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular, biologically active lysophosphatidic acid (LPA), a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability, we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One, we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two, we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling, namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.