SUN-079 Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation

Abstract

Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1), a substrate of insulin and VEGF receptors, regulates insulin sensitivity by promoting hepatic insulin clearance. Global Ceacam1 gene deletion impaired insulin clearance to cause chronic hyperinsulinemia and peripheral insulin resistance [1]. It also caused spontaneous endothelial dysfunction and hypertension [2] in addition to atherogenic-like plaques in addition to lipid and macrophage deposition, as well as elevated leukocyte rolling and adhesion to the aortic wall in the absence of hypercholesterolemia and hypertriglyceridemia when the mutation was propagated on the C57BL/6 genetic background [3]. Because CEACAM1 promotes endothelial survival, vascular integrity, and pro-angiogenesis, we investigated the cell-autonomous role of endothelial cell CEACAM1 in the pathogenesis of atherosclerosis. To this aim, we generated endothelial cell CEACAM1 knockout mice and backcrossed them with low density lipoprotein receptor deficient mice (ldlr–/– VECad+Cc1fl/fl) prior to feeding them a high cholesterol diet for 3 months and characterizing both of their metabolic and vascular phenotypes. By comparison to ldlr–/– mice, the mutants exhibited insulin sensitivity and moderate hypercholesterolemia. However, they exhibited decreased nitric oxide (NO) bioavailability with a reciprocal increase in plasma endothelin-1 and increased oxidative stress. The mutants also developed fibrotic plaques with elevated macrophage recruitment on the aortic wall without lipid deposition. We postulate that endothelin-1 contributes to fibrosis in these mice. Elevated endothelin-1 levels could stem from increased ras-MAPKinase signaling pathways in response to lower sequestration of Shc and increased coupling of Grb2 to insulin and VEGR in the absence of Ceacam1. Moreover, in the absence of Ceacam1, binding of Shp2 phosphatase to IRS1 increases to reduce IRS-1/Akt/eNOS activity and subsequently, lower NO production. Thus, the ldlr–/– VECad+Cc1fl/fl mouse can provide an in vivo system to delineate the endothelial cell-specific CEACAM1 effect on fibrosis independent of systemic risk factors.