CEACAM1: A link between metabolic and cardiovascular diseases

CEACAM1：代谢与心血管疾病之间的联系

• 批准号: 8403751
• 负责人: Sonia M. Najjar
• 金额: $ 35.73万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403751
• 关键词: Ablation; Address; Adipose tissue; Animal Model; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Vessels; Cardiovascular Diseases; Cattle; Cause of Death; Cell physiology; Cells; Central obesity; Cholesterol; Clinical Research; Data; Development; Diet; Disease; Dyslipidemias; Endothelial Cells; Exhibits; Experimental Models; Eye; Fatty Acids; Functional disorder; Genes; Hepatic; Hepatocyte; Hyperinsulinism; Hyperlipidemia; Incidence; Indium; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knockout Mice; LDL Cholesterol Lipoproteins; Link; Lipids; Liver; Low Density Lipoprotein Receptor; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Play; Predisposition; Production; Regulation; Reporting; Role; Serum; Signal Transduction; Site; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Triglycerides; United States; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilation; Very low density lipoprotein; Work; atherogenesis; base; carcinoembryonic antigen-related cell adhesion molecules; cell type; feeding; gain of function; high risk; human NOS3 protein; in vivo; innovation; insulin sensitivity; insulin signaling; lipid biosynthesis; loss of function; mouse model; prevent; response

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.

患有代谢性疾病的人患动脉粥样硬化的风险更高，动脉粥样硬化是心脏病的主要原因