Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice
Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice
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DOI：
10.1161/01.res.0000028008.99774.7f
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发表时间：
2002-07-26
影响因子：
20.1
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
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作者：
Mehrabian, M;Allayee, H;Lusis, AJ
我们之前曾报道过在小鼠6号染色体上发现了一个几乎完全抵抗动脉粥样硬化形成的基因，即使是在高胆固醇血症(低密度脂蛋白受体缺失)的背景下也是如此。5-脂氧合酶(5-LO)是白三烯合成的限速酶，也是我们研究的6号染色体候选基因之一。与背景株C57BL/6J(136)相比，含有来自CAST/EI株(CAST)的抗性6号染色体区域的同源株CON6的5-LO基因表达水平降低了约5倍。5-LO蛋白水平在CON6小鼠中也有类似的降低。对5-LO基因的序列分析表明，CON6和136株之间存在一些差异。为了测试5-LO是否与耐药表型有关，我们在低密度脂蛋白受体缺失(LDLR-/-)的背景上培育了一个5-LO基因敲除等位基因。在此背景下，小鼠繁殖不良，仅获得杂合子5-LO基因敲除小鼠。这些小鼠的数量显著减少(>；26倍；P
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 (136) 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 136 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