Disruption of Tissue-Specific Fucosyltransferase VII, an Enzyme Necessary for Selectin Ligand Synthesis, Suppresses Atherosclerosis in Mice

Jonathan M. Gitlin^*, Jonathon W. Homeister, Joshua Bulgrien^*, Jessica Counselman^*, Linda K. Curtiss^*, John B. Lowe and William A. Boisvert^*

From the Department of Immunology,^* The Scripps Research Institute, La Jolla, California; the University of North Carolina, Chapel Hill, North Carolina; and the Department of Pathology, Case Western Reserve University, Cleveland, Ohio

A hallmark feature of atherosclerosis is that circulating mononuclearcells adhere to the endothelium and migrate into the subendothelialspace. This adhesion is mediated by molecules such as selectinsthat are expressed on the surfaces of both leukocytes and endothelialcells. In this study, we have determined the role of tissue-specificfucosyltransferase VII (FucT-VII), an enzyme necessary for selectinligand synthesis, in the development of atherosclerosis. Weadopted a scheme of transplanting either FucT-VII^–/–GFP⁺bone marrow into lethally irradiated low-density lipoproteinreceptor low density lipoprotein receptor mice or FucT-VII^+/+GFP⁺ bone marrow into FucT-VII^–/–, low density lipoproteinreceptor double-mutant mice to evaluate the roles of E- andP-selectin ligands versus L-selectin ligands, respectively,in diet-induced atherosclerosis. GFP was used to track the transplantedcells. Our results indicate that, compared with controls, selectivedisruption of E- and P-selectin ligand synthesis resulted ina significant reduction in atherosclerosis. Selective disruptionof L-selectin ligand production did not reduce atherosclerosisas robustly as disruption of E- and P-selectin ligands. In bothgroups, however, there was a significant reduction in the accumulationof macrophages in the lesion. These studies indicate that selectinligands, particularly those for E- and P-selectins, play animportant role in the pathogenesis of atherosclerosis by regulatingmacrophage accumulation in atherosclerotic lesions.