PubMed:12142344
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/12142344","sourcedb":"PubMed","sourceid":"12142344","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/12142344","text":"Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.\nWe 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 (\u003e26-fold; P\u003c0.0005) 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.","tracks":[{"project":"2015-BEL-Sample","denotations":[{"id":"T1","span":{"begin":1641,"end":1871},"obj":"cat(p(MGI:Alox5)) increases path(MESHD:Atherosclerosis)"}],"attributes":[{"subj":"T1","pred":"source","obj":"2015-BEL-Sample"}]},{"project":"2015-BEL-Sample-2","denotations":[{"id":"BEL:20000422","span":{"begin":1641,"end":1871},"obj":"cat(p(MGI:Alox5)) increases path(MESHD:Atherosclerosis)"}],"attributes":[{"subj":"BEL:20000422","pred":"source","obj":"2015-BEL-Sample-2"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2015-BEL-Sample","color":"#93e0ec","default":true},{"id":"2015-BEL-Sample-2","color":"#ecde93"}]}]}}