Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.
Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.
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DOI：
10.1073/pnas.87.18.6959
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发表时间：
1990-09
影响因子：
11.1
通讯作者：
Seppo Ylä-Herttuala;Michael E. Rosenfeld;S. Parthasarathy;Christopher K. Glass;Elliott Sigal;J. L. Witztum
中科院分区：
文献类型：
--
作者：
Seppo Ylä-Herttuala;Michael E. Rosenfeld;S. Parthasarathy;Christopher K. Glass;Elliott Sigal;J. L. Witztum
低密度脂蛋白（LDL）的氧化增强其致动脉粥样硬化性，而抑制这种氧化可降低动脉粥样硬化病变的进展速度。体内 LDL 氧化的机制仍不确定，但体外研究表明细胞脂氧合酶可能通过引发 LDL 中的脂质过氧化而发挥作用。使用 15-脂氧合酶核糖核酸探针进行的原位杂交研究和使用抗 15-脂氧合酶抗体的免疫染色显示，强阳性反应性主要局限于动脉粥样硬化病变的富含巨噬细胞的区域。使用 15-脂氧合酶特异性寡核苷酸的聚合酶链反应和扩增片段的限制酶消化来确认逆转录损伤 mRNA 中 15-脂氧合酶信息的存在。使用与氧化的 LDL（但不与天然 LDL）反应的抗体进行的免疫染色表明，脂氧合酶与氧化的 LDL 的表位共定位，这与巨噬细胞脂氧合酶在体内 LDL 氧化中的作用相一致。由于氧化的低密度脂蛋白对血液单核细胞具有趋化性，因此早期病变可能会以明显加快的速度进展，因为更多的单核细胞会进一步募集，这反过来又会进一步增加低密度脂蛋白的氧化速度。这些数据表明，针对阻断巨噬细胞脂氧合酶活性的治疗可能会降低动脉粥样硬化病变的发展速度。
Oxidation of low density lipoprotein (LDL) enhances its atherogenicity, and inhibition of such oxidation decreases the rate of progression of atherosclerotic lesions. The mechanism of LDL oxidation in vivo remains uncertain, but in vitro studies have suggested that cellular lipoxygenases may play a role by initiating lipid peroxidation in LDL. In situ hybridization studies using a 15-lipoxygenase riboprobe and immunostaining using antibodies against 15-lipoxygenase showed strongly positive reactivity largely confined to macrophage-rich areas of atherosclerotic lesions. Polymerase chain reaction with 15-lipoxygenase-specific oligonucleotides and restriction enzyme digestions of the amplified fragment were used to confirm the presence of 15-lipoxygenase message in the reverse-transcribed lesion mRNA. Immunostaining with antibodies reactive with oxidized LDL (but not with native LDL) indicated that the lipoxygenase colocalizes with epitopes of oxidized LDL, compatible with a role for macrophage lipoxygenase in the oxidation of LDL in vivo. Since oxidized LDL is chemotactic for blood monocytes, early lesions might progress at a markedly accelerated rate because of further recruitment of more monocytes which, in turn, would increase further the rate of oxidation of LDL. These data suggest that therapy targeted to block macrophage lipoxygenase activity might decrease the rate of development of atherosclerotic lesions.