α(1,3)fucosyltransferases FucT-IV and FucT-VII control susceptibility to atherosclerosis in apolipoprotein E-/- mice

Objective - These studies examine the contributions of α(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 α(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.