Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.
We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor-null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor-null (LDLR(-/-)) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold; P<0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE(-/-) and LDLR(-/-) deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO(+/-) mice was transplanted into LDLR(-/-), there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.
Mehrabian
Margarete
M
Department of Medicine, UCLA School of Medicine, Los Angeles, Calif 90095-1679, USA. mmehrabi@ucla.edu
Allayee
Hooman
H
Wong
Jack
J
Shi
Weibin
W
Wang
Xu-Ping
XP
Shaposhnik
Zory
Z
Funk
Colin D
CD
Lusis
Aldons J
AJ
Shih
Weibin
W
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000502:physiology; D001161:Arteriosclerosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016026:Bone Marrow Transplantation; D020022:Genetic Predisposition to Disease; D007328:Insulin / Q000097:blood; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000235:genetics
D007328:Insulin; D012333:RNA, Messenger; D011973:Receptors, LDL; D001094:Arachidonate 5-Lipoxygenase