Alpha(1,3)fucosyltransferases FucT-IV and FucT-VII control susceptibility to atherosclerosis in apolipoprotein E-/- mice.
OBJECTIVE
These studies examine the contributions of alpha(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.


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 alpha(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.
Department of Pathology and The Howard Hughes Medical Institute, University of Michigan, M5240 Medical Science I, 1301 Catherine Street, Ann Arbor, MI 48109-0602, USA. homeiste@umich.edu.
Jonathon W
JW
Homeister
Alan
A
Daugherty
John B
JB
Lowe
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003433:Crosses, Genetic; D004198:Disease Susceptibility / Q000097:blood / Q000201:enzymology; D019040:E-Selectin / Q000378:metabolism; D005647:Fucosyltransferases / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D007958:Leukocyte Count; D007964:Leukocytosis / Q000097:blood / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism
D001057:Apolipoproteins E; D019040:E-Selectin; D019007:P-Selectin; D005647:Fucosyltransferases; C031692:galactoside 3-fucosyltransferase