CEACAM1: A link between metabolic and cardiovascular diseases

患有代谢性疾病的人患动脉粥样硬化的风险更高，动脉粥样硬化是 死亡在美国和世界范围内。早期的研究已经将血脂异常与启动和 动脉粥样硬化的进展。然而，最近的临床研究引发了人们对阿司匹林疗效的担忧。 降低动脉粥样硬化进展中的血浆胆固醇水平。尽管胰岛素抵抗是 与心血管疾病发病率增加有关，无论是导致动脉粥样硬化 与其伴发的血脂异常无关，目前仍不清楚，主要是因为缺乏 合适的动物模型来解决这个问题。癌胚抗原相关细胞黏附 分子-1(CEACAM1)通过促进肝脏对胰岛素的清除来调节胰岛素敏感性。因此， Ceacam1基因的全球零缺失损害肝脏的胰岛素清除并导致高胰岛素血症， 这反过来会导致全身性胰岛素抵抗。初步数据显示：(1)全球Cc1-/-空 即使在正常喂养下，小鼠也会出现早期动脉粥样硬化病变和血管功能障碍 (2)这种情况发生在没有高脂血症的情况下，尽管极低密度脂蛋白/低密度脂蛋白胆固醇 通常与动脉粥样硬化消退相关的水平，而不是与发展相关的水平。这种独特的动物 无高脂血症时单纯胰岛素抵抗的动脉粥样硬化形成模型 高胰岛素血症引起的全身性胰岛素抵抗会导致血管功能障碍和 动脉粥样硬化在没有高脂血症的情况下。因为CEACAM1被两种胰岛素磷酸化 血管内皮生长因子受体调节内皮型一氧化氮合酶(ENOS)Akt1的激活，eNOS是一种重要的 在调节内皮功能方面，有理由认为CEACAM1是共享的 血管内皮生长因子下游元件与内皮细胞胰岛素信号转导失活 影响这两个途径，并导致胰岛素抵抗中的内皮功能障碍。为了测试 这一假说，CEACAM1对胰岛素沿肝脏/内皮细胞轴的调节作用 将会被调查。目的1检查高胰岛素血症是否由肝脏胰岛素受损引起 清除，改变内皮细胞中的胰岛素活动，并以这种细胞非自主的方式，启动 动脉粥样硬化的发展。AIM 2检查是否通过依赖CEACAM1的信号改变 通路扰乱内皮细胞对胰岛素和血管内皮生长因子的反应，在这个细胞中-自主 时尚，导致内皮功能障碍，并引发动脉粥样硬化。调查……的具体作用 肝和内皮细胞CEACAM1在动脉粥样硬化和血管功能障碍发病机制中的作用 将使用一套新产生的独特的功能丧失和功能获得的动物模型。 回答这些问题将勾勒出依赖CEACAM1的新机制 沿着肝脏/内皮细胞轴的动脉粥样硬化，并精确地指出药物干预的部位。

Individuals with metabolic diseases are at a higher risk of developing atherosclerosis, a leading cause of death in the United States and worldwide. Earlier studies have linked dyslipidemia to the initiation and progression of atherosclerosis. However, recent clinical studies raised concerns about the efficacy of lowering plasma cholesterol levels in the progression of atherosclerosis. Although insulin resistance is associated with increased incidence of cardiovascular disease, whether it leads to atherosclerosis independently of its accompanying dyslipidemia remains unclear, largely because of the lack of a suitable animal model to address this question. The CarcinoEmbryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) regulates insulin sensitivity by promoting insulin clearance in liver. Accordingly, global null deletion of Ceacam1 gene impairs hepatic insulin clearance and causes hyperinsulinemia, which in turn, results in systemic insulin resistance. Preliminary data show: (i) that global Cc1-/- null mice develop early atherosclerotic lesions and vascular dysfunction even under normal feeding conditions, and (ii) that this occurs in the absence of hyperlipidemia, despite VLDL/LDL cholesterol levels that are usually associated with atherosclerosis regression, not development. This unique animal model of atherogenesis with isolated insulin resistance in the absence of hyperlipidemia demonstrates that systemic insulin resistance resulting from hyperinsulinemia leads to vascular dysfunction and atherosclerosis in the absence of hyperlipidemia. Because phosphorylation of CEACAM1 by both insulin and VEGF receptors regulates Akt1 activation of endothelial Nitric Oxide Synthase (eNOS), an essential step in mediating endothelial function, it is reasonable to propose that CEACAM1 is the shared downstream element in VEGF and insulin signaling in endothelial cells, whose inactivation impinges upon both pathways and causes endothelial dysfunction in insulin resistance. To test this hypothesis, the regulatory effect of CEACAM1 on insulin action along the liver/endothelial cell axis will be investigated. Aim 1 examines whether hyperinsulinemia caused by impaired hepatic insulin clearance, alters insulin action in the endothelial cell, and in this cell-nonautonomous fashion, initiates atheroma development. Aim 2 examines whether altered signaling through CEACAM1-dependent pathways disrupts the endothelial cell's response to insulin and VEGF, and in this cell-autonomous fashion, drives endothelial dysfunction and initiates atherosclerosis. To investigate the specific role of hepatic and endothelial cell CEACAM1 in the pathogenesis of atherosclerosis and vascular dysfunction, a newly generated set of unique animal models of loss-of-function and gain-of-function will be used. Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention.