Cyrus T, Witztum J L, Rader D J, Tangirala R, Fazio S, Linton M F, Funk C D
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 1999 Jun;103(11):1597-604. doi: 10.1172/JCI5897.
Atherosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This "oxidation hypothesis" has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/-/L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198 +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E-deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.
动脉粥样硬化可被视为一种炎症性疾病过程，其中包括低密度脂蛋白（LDLs）的早期氧化修饰，进而导致泡沫细胞形成。近年来，这种“氧化假说”已得到广泛认可，并且关于脂氧合酶在氧化过程起始或参与方面作用的证据也在不断积累。然而，巨噬细胞表达的脂氧合酶在体内动脉粥样硬化发生中的相对贡献仍不清楚。在此，我们提供了体内证据，证明12/15-脂氧合酶在动脉粥样硬化发生中的作用，并表明与易患动脉粥样硬化的载脂蛋白E缺陷小鼠（apo E-/-/L-12LO-/-）杂交的12/15-脂氧合酶基因敲除小鼠中，针对氧化LDL表位的血浆IgG自身抗体减少。在喂食普通饲料的15周龄apo E-/-/L-12LO-/-小鼠中，与表达12/15-脂氧合酶的对照小鼠（apo E-/-/L-12LO+/+）相比，整个主动脉标本中病变范围（198±60平方微米）显著减少（P<0.001，n = 12），后者在主动脉弓小弯侧、分支点和腹主动脉处出现脂质沉积区域（15700±2688平方微米）。尽管胆固醇、甘油三酯和脂蛋白水平与apo E缺陷小鼠相似，但仍观察到了这些结果。即使在apo E-/-/L-12LO-/-小鼠1岁时，也观察到了病变发展减少的证据。综合数据表明12/15-脂氧合酶在动脉粥样硬化发病机制中起作用，并提示抑制该酶可能会减缓疾病进展。
