CEACAM1: A link between metabolic and cardiovascular diseases

患有代谢性疾病的个体患动脉粥样硬化的风险更高，动脉粥样硬化是导致糖尿病的主要原因。 死亡在美国和世界各地。早期的研究已经将血脂异常与开始和 动脉粥样硬化的进展。然而，最近的临床研究引起了对 降低动脉粥样硬化进展中的血浆胆固醇水平。虽然胰岛素抵抗是 与心血管疾病的发病率增加有关，无论它是否导致动脉粥样硬化 独立于其伴随的血脂异常仍然不清楚，主要是因为缺乏一个 合适的动物模型来解决这个问题。癌胚抗原相关的细胞粘附 分子-1（CEACAM 1）通过促进肝脏中的胰岛素清除来调节胰岛素敏感性。因此，委员会认为， Ceacam 1基因的整体无效缺失损害肝脏胰岛素清除并引起高胰岛素血症， 这又导致全身性胰岛素抵抗。初步数据显示：（i）全局Cc 1-/- null 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 条件下，和（ii）这发生在不存在高脂血症，尽管VLDL/LDL胆固醇 这些水平通常与动脉粥样硬化的消退有关，而不是发展。这种独特的动物 在没有高脂血症的情况下，具有孤立胰岛素抵抗的动脉粥样硬化形成模型表明， 由高胰岛素血症引起的全身性胰岛素抵抗导致血管功能障碍， 动脉粥样硬化在没有高脂血症。因为CEACAM 1的磷酸化被胰岛素 和VEGF受体调节内皮型一氧化氮合酶（eNOS）的Akt 1活化， 在介导内皮功能的步骤，这是合理的建议，CEACAM 1是共享的 血管内皮细胞中VEGF和胰岛素信号传导的下游元件，其失活 影响两种途径并导致胰岛素抵抗中的内皮功能障碍。测试 这一假设，CEACAM 1对胰岛素作用的调节作用沿着肝/内皮细胞轴 将被调查。目的1探讨高胰岛素血症是否由肝胰岛素受损引起 清除，改变胰岛素在内皮细胞中的作用，并以这种细胞非自主的方式启动 动脉粥样化发展。目的2检查是否通过CEACAM 1依赖性改变信号传导 通路破坏了内皮细胞对胰岛素和VEGF的反应，并且在这种细胞自主的 时尚，驱动内皮功能障碍并引发动脉粥样硬化。为了研究的具体作用 肝和内皮细胞CEACAM 1在动脉粥样硬化和血管功能障碍的发病机制中， 将使用一组新产生的功能丧失和功能获得的独特动物模型。 阐明这些问题将揭示新的CEACAM 1依赖性机制， 沿着肝/内皮细胞轴的动脉粥样硬化，以及药物干预的精确定位。

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.