Loss of CEACAM1 in the pathogenesis of vascular abnormalities associated with the metabolic syndrome.

摘要

The metabolic syndrome is associated with an increased risk for cardiovascular disease. Defining a mechanistic link between these diseases has been limited by the lack of an experimental model that completely mimics the human state. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin and lipid metabolism in liver, down regulates inflammatory response in activated T-lymphocytes, modulates epidermal growth factor receptor (EGFR) mediated signalling, and preserves the endothelium through its role in angiogenesis. Null mutation of Ceacam1 (Cc1--/-- ) results in insulin resistance due to impaired insulin clearance, resulting in visceral obesity, dyslipidemia, and hepatic steatosis due to elevated triglyceride and cholesterol synthesis, and high plasma triglyceride and fatty acid levels. The goal of this work was to test whether loss of CEACAM1 also results in cardiovascular disease. We herein characterized the cardiovascular phenotype of the Cc1--/-- mice.;Histological examination of the vasculature revealed that at six months the Cc1--/-- mice develop spontaneous atherosclerotic lesions. In addition, six month old Cc1 --/-- mice exhibit modest plasma hypercholesterolemia, elevated markers of vascular inflammation measured by quantitative real-time PCR, oxidative stress, and endothelial dysfunction all factors associated with atherosclerosis. We herein report that the Cc1--/-- mice provide a novel model to study the mechanistic relationship between metabolic abnormalities, endothelial dysfunction, and atherosclerosis, and also highlight CEACAM1 with a potential mechanistic role linking metabolic abnormalities, endothelial dysfunction, and atherosclerosis. Six month old Cc1 --/-- mice were also found to be hypertensive, indicating that they are a novel mouse model of the metabolic syndrome. This rise in blood pressure was associated with an elevated activation of the renin angiotensin system (RAS). Further examination of the Cc1--/-- mice kidneys revealed evidence of renal inflammation and fibrosis. This data highlights CEACAM1 as a novel mechanistic link between metabolic abnormalities, hypertension, and the up regulation of the RAS.;The presented work promotes the Cc1--/-- mouse as a novel model to investigate the mechanistic link between the metabolic syndrome and the pathogenesis of the cardiovascular diseases, as well as identify CEACAM1 as a potential molecular target of these disorders.