CEACAM1: A link between metabolic and cardiovascular diseases

描述(由申请人提供)：患有代谢性疾病的人患动脉粥样硬化的风险更高，动脉粥样硬化是美国和世界范围内的主要死亡原因。早期的研究已将血脂异常与动脉粥样硬化的发生和发展联系起来。然而，最近的临床研究引起了人们对降低血浆胆固醇水平在动脉粥样硬化进展中的有效性的关注。尽管胰岛素抵抗与心血管疾病的发病率增加有关，但它是否会导致动脉粥样硬化独立于其伴随的血脂异常尚不清楚，这主要是因为缺乏合适的动物模型来解决这一问题。癌胚抗原相关细胞黏附分子-1(CEACAM1)通过促进胰岛素在肝脏的清除来调节胰岛素敏感性。因此，Ceacam1基因的全球零缺失会损害肝脏的胰岛素清除，导致高胰岛素血症，进而导致全身性胰岛素抵抗。初步数据显示：(I)全球CC1/缺失小鼠即使在正常喂养条件下也会出现早期动脉粥样硬化病变和血管功能障碍，(Ii)这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水平通常与动脉粥样硬化的消退有关，而不是与发展有关。这种在没有高脂血症的情况下单独存在胰岛素抵抗的动脉粥样硬化形成的独特动物模型表明，由高胰岛素血症引起的全身性胰岛素抵抗在没有高脂血症的情况下会导致血管功能障碍和动脉粥样硬化。由于CEACAM1被胰岛素和血管内皮细胞生长因子受体同时磷酸化，调节内皮型一氧化氮合酶(ENOS)Akt1的激活，这是介导内皮功能的一个重要步骤，因此有理由认为CEACAM1是血管内皮生长因子和胰岛素信号通路中共有的下游元件，其失活影响这两条途径，导致胰岛素抵抗时内皮细胞功能障碍。为了验证这一假设，我们将研究CEACAM1对沿肝脏/内皮细胞轴的胰岛素作用的调节作用。目的1研究肝脏胰岛素清除受损引起的高胰岛素血症是否会改变内皮细胞的胰岛素作用，并以这种细胞非自主的方式启动动脉粥样硬化的发展。目的2研究通过CEACAM1依赖的通路改变的信号是否扰乱内皮细胞对胰岛素和血管内皮生长因子的反应，并在这种细胞自主的方式下，推动内皮功能障碍和启动动脉粥样硬化。为了研究肝脏和内皮细胞CEACAM1在动脉粥样硬化和血管功能障碍发病机制中的具体作用，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沿着肝脏/内皮细胞轴导致动脉粥样硬化的新的CEACAM1依赖机制，并准确地指出药物干预的部位。 公共卫生相关性：患有代谢综合征的人患动脉粥样硬化的风险更高，动脉粥样硬化是美国的主要死亡原因。基于降低血胆固醇的策略已被证明在阻止代谢综合征患者动脉粥样硬化进展方面的价值有限。在CEACAM1在调节肝脏胰岛素代谢中的作用的开创性工作的基础上，现在提出了新的令人信服的证据，将其在系统性胰岛素抵抗中的调节作用与动脉粥样硬化的发病机制联系起来。这项提议试图探索这种机制上的联系，着眼于开发一种更有效的治疗策略来对抗这种疾病。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Individuals with metabolic syndrome are at a higher risk of developing atherosclerosis, a leading cause of death in the United States. A strategy based on lowering blood cholesterol has been shown to be of limited value in stopping progression of atherosclerosis in patients with metabolic syndrome. Building on the pioneering work on the role of CEACAM1 in the regulation of insulin metabolism in liver, new compelling evidence is now presented to link its regulatory role of systemic insulin resistance to the pathogenesis of atherosclerosis. This proposal seeks to explore this mechanistic link with an eye on developing a more effective therapeutic strategy against the disease.