Adiponectin Actions on the Monocyte to Reduce Atherosclerosis

描述（由申请人提供）：脂联素是一种主要由脂肪组织产生的激素，已成为西方世界两种主要疾病糖尿病和心血管疾病的治疗靶点。脂联素具有抗糖尿病、降血脂和抗动脉粥样硬化的特性，但在肥胖、胰岛素抵抗、2型糖尿病和心血管疾病中以低水平循环。虽然越来越多的数据表明脂联素在血管细胞中的多效性作用，但脂联素和脂联素受体表达在单核细胞/巨噬细胞炎症和致动脉粥样硬化性质中的作用仍不清楚。我们已经产生了令人兴奋的新数据，表明1）胰岛素抵抗与胰岛素敏感受试者的单核细胞具有更多的促炎基因表达，2）两种脂联素受体都在单核细胞上表达，并且在胰岛素抵抗中增加，3）脂联素激活单核细胞5'腺苷单磷酸激活激酶（AMPK），抑制由肿瘤坏死因子-1激活的炎性基因，和4）腺病毒脂联素的施用抑制小鼠模型中加速的动脉粥样硬化并促进现有动脉粥样硬化的消退。该项目的主要假设是血浆脂联素的改变与单核细胞/巨噬细胞基因的关键变化相关，单核细胞/巨噬细胞基因介导炎症、泡沫细胞形成并最终影响血管炎症、动脉粥样硬化进展和消退。该项目的具体目标是：1）确定调节单核细胞/巨噬细胞中的脂联素受体AdipoR 1和AdipoR 2的特异性炎症和代谢因子，2）确定调节单核细胞/巨噬细胞功能、炎症基因表达的脂联素基因靶标，和泡沫细胞的形成，并确定AMPK和过氧化物酶体增殖物激活受体（PPAR）的作用。1信号通路在这些过程中的作用，和3）确定腺病毒脂联素和脂联素依赖性PPAR 3配体在加速动脉粥样硬化进展（血管紧张素II输注的LDLR-/-和旧-LDLR-/-）和消退（旧-LDLR-/-）模型中的作用，以及巨噬细胞脂联素受体在血管炎症和动脉粥样硬化中的作用，使用AdipoR 1/R2敲除小鼠的骨髓移植。该项目对于确定脂联素及其受体在单核细胞/巨噬细胞中的特异性保护作用，识别脂联素在单核细胞/巨噬细胞中潜在的新候选基因靶点，以及确定这些基因在小鼠心血管疾病模型中减缓动脉粥样硬化进展或促进动脉粥样硬化消退中的作用将是重要的。本文提出的研究将为我们理解脂联素提供重要的新见解，其作为代谢综合征治疗靶点的潜在重要性，以及其对糖尿病和冠状动脉疾病的影响。

DESCRIPTION (provided by applicant): Adiponectin, a hormone produced primarily by adipose tissue, has emerged as a therapeutic target for two major diseases of the Western World, diabetes and cardiovascular disease. Adiponectin has antidiabetic, antiinflammatory and antiatherogenic properties, but circulates in low levels in obesity, insulin resistance, type 2 diabetes and cardiovascular disease. Although increasing data demonstrate pleiotropic effects of adiponectin in vascular cells, the role of adiponectin and adiponectin receptor expression in monocyte/macrophage inflammatory and atherogenic properties remain unclear. We have generated exciting new data demonstrating that 1) monocytes of insulin resistant vs. insulin sensitive subjects have more proinflammatory gene expression, 2) both adiponectin receptors are expressed on the monocyte and are increased in insulin resistance, 3) adiponectin activates monocyte 5' adenosine mono phosphate-activated kinase (AMPK) suppressing inflammatory genes activated by tumor necrosis factor-1, and 4) administration of adenoviral adiponectin inhibits accelerated atherosclerosis and promotes regression of existing atherosclerosis in mouse models. The major hypothesis of this project is that alterations in plasma adiponectin are associated with key changes in monocyte/macrophage genes that mediate inflammation, foam cell formation and that ultimately influence vascular inflammation, atherosclerosis progression and regression. The specific aims of this project are to: 1) define specific inflammatory and metabolic factors that regulate the adiponectin receptors, AdipoR1 and AdipoR2 in monocyte/macrophages, 2) define adiponectin gene targets that regulate monocyte/macrophage function, inflammatory gene expression, and foam cell formation in human and mouse monocyte/macrophages and determine the role of the AMPK and peroxisome proliferator activated receptor(PPAR)-1 signaling pathways in these processes, and 3) determine adenoviral adiponectin and adiponectin-dependent PPAR3 ligand effects in models of accelerated atherosclerosis progression (angiotensin II-infused LDLR-/- and old-LDLR-/-) and regression (old-LDLR-/-), and the role of macrophage adiponectin receptors in vascular inflammation and atherosclerosis using bone marrow transplantation with AdipoR1/R2 knockout mice. This project will be important to define specific protective actions of adiponectin and its receptors in the monocyte/macrophage; to identify potentially new candidate gene targets of adiponectin in monocyte/macrophages; and to define the role of these genes in attenuating the progression or promoting the regression of atherosclerosis in mouse cardiovascular disease models. The studies proposed herein will provide important new insights into our understanding of adiponectin, its potential importance as a therapeutic target in the metabolic syndrome, and its consequences for diabetes and coronary artery disease.