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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1897.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

(1,3)Fucosyltransferases FucT-IV and FucT-VII Control Susceptibility to Atherosclerosis in Apolipoprotein E–/– Mice

Jonathon W. Homeister; Alan Daugherty; John B. Lowe

From the Department of Pathology and The Howard Hughes Medical Institute (J.W.H., J.B.L.), University of Michigan, Ann Arbor, Mich; and the Department of Medicine (A.D.), Gill Heart Institute, University of Kentucky, Lexington.

Correspondence to Dr Jonathon W. Homeister, Department of Pathology, University of Michigan, M5240 Medical Science I, 1301 Catherine Street, Ann Arbor, MI 48109-0602. E-mail homeiste{at}umich.edu

Objective— These studies examine the contributions of (1,3)fucosyltransferases (FucT) IV and VII to the generation of selectin counter-receptors necessary for selectin-dependent atherogenesis. They also determine the functional contribution of FucT-IV and FucT-VII to shear-dependent tethering of monocytes to P-selectin, a process believed to be required for atherogenesis.

Methods and Results— Atherosclerotic lesion size and histology were determined in apolipoprotein E–/– mice sufficient or deficient in FucT-IV or FucT-VII. Lesion size was subtly reduced in FucT-IV–deficient mice and significantly reduced in FucT-VII–deficient mice. FucT deficiency did not alter lesion histology, plasma total cholesterol, or the lipoprotein distribution profile. Atheroprotection in FucT-IV or FucT-VII deficiency aligned with subtle and profound reductions, respectively, of P-selectin counter-receptor activity on peripheral blood monocytes as determined by tethering to P-selectin-IgG in vitro under shear flow.

Conclusions— FucT-VII–mediated (1,3)fucosylation of selectin ligands is a necessary concomitant to atherogenesis in apoE–/– mice and is required for P-selectin–dependent peripheral blood monocyte adhesion under shear stress. FucT-IV deficiency yields subtle deficits in monocyte P-selectin counter-receptor activity and is associated with a subtle decrement in atherosclerosis. These studies identify an important role for FucT-VII in atherogenesis, and a subsidiary role for FucT-IV, and implicate leukocyte selectin counter-receptors in the pathogenesis of atherosclerosis.

Roles for leukocyte selectin ligands in atherogenesis are implied by atheroprotection in selectin-deficient mice. In apoE–/– mice, deficiency of (1,3)fucosyltransferase IV or VII leads to subtle or marked atheroprotection, respectively, and corresponding reductions in monocyte P-selectin counter-receptor activity. These observations assign (1,3)fucosyltransferases IV and VII to controlling roles in atherogenesis.

Key Words: atherosclerosis • apolipoprotein E • fucosyltransferase • monocyte • selectin

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