Contribution of CEACAM1 to the pathogenesis of atherosclerosis – mechanisms and therapeutic approaches

• Applicant: Dr. Florian Kleefeldt
• Subject Area: Anatomy and Physiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502291066

Atherosclerosis-associated diseases, i.e. myocardial infarction and stroke are one of the leading causes of death worldwide. Although a subject of intensive investigations, efficient pharmacological interventions to prevent atherosclerosis are still lacking.Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; Cc1) is a member of the immunoglobulin superfamily. Own preliminary data show that CEACAM1 is selectively upregulated within the endothelium covering the atherosclerotic plaque. Furthermore, using the atherosclerosis model of Western Diet-fed low density lipoprotein receptor-deficient mice (Ldlr-/-) we demonstrated for the first time that CEACAM1 deficiency (Ldlr-/-/Cc1-/-) reduces the degree of plaque formation by more than 50%. In contrast, endothelium-specific re-expression of CEACAM1 in these mice (Ldlr-/-/Cc1-/-/ER) doubles atherosclerotic lesion size. These data impressively document a hitherto unrecognized central role of CEACAM1 in the pathogenesis of atherosclerosis.The requested project aims to discover in detail how endothelial CEACAM1 affects atherosclerotic plaque formation and composition. To this end, the influence of CEACAM1 on central aspects of atherosclerosis pathogenesis will be analyzed i.e. vascular inflammation, oxidative stress, monocyte adhesion and uptake of oxidatively modified LDL. Furthermore, anti-CEACAM1-antibodies will be tested to visualize atherosclerotic lesions in vivo.For mechanistically analyses in vitro, endothelial cell lines with and without CEACAM1 expression are available to us. For in vivo analysis, we will use the above mentioned Ldlr-/- murine model of atherosclerosis with different CEACAM1 expression profiles: unaltered CEACAM1 expression (Ldlr-/-), global CEACAM1 deficiency (Ldlr-/-/Cc1-/-) and global CEACAM1 deficiency with endothelial CEACAM1 re-expression (Ldlr-/-/Cc1-/-/ER). These mouse strains will enable the differential analysis of CEACAM1’s role in atherosclerotic plaque formation as well as validation of in vitro key results. All intended methods are established at the applicant’s working group. A few analyses will be conducted externally (Core Facilities, Julius Maximilians University, Wuerzburg).It is expected that the results of the requested project will establish CEACAM1 as a crucial marker and mediator of atherosclerotic processes thereby providing novel options in diagnosis, prophylaxis and therapy of atherosclerosis.

• DFG Programme: Research Grants