Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia - Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions
Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia - Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions
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DOI：
10.1172/jci119813
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发表时间：
1997-12-01
影响因子：
15.9
通讯作者：
Palinski, W
中科院分区：
文献类型：
--
作者：
Napoli, C;D'Armiento, FP;Palinski, W
为了确定氧化LDL是否通过促进单核细胞聚集到血管内膜而增强动脉粥样硬化的发生，我们研究了人胎儿动脉粥样硬化中LDL的积聚和氧化是否先于单核细胞的内膜积聚（来自自然流产和12小时内死亡的早产儿;胎龄6.2+/-1.3个月），为此，进行系统评估：在来自正常胆固醇血症母亲（n = 22）、高胆固醇血症母亲（n = 33）和仅在妊娠期间高胆固醇血症的母亲（n = 27）的胎儿胎盘中进行脂肪条纹形成tvas，胎儿血浆胆固醇水平与胎龄呈强负相关6月龄以内胎儿血浆胆固醇水平与母体血浆胆固醇水平呈显著正相关（R =-0.88，P < 0.0001）（R = 0.86，P = 0.001），而在年龄较大的胎儿没有这种相关性存在。高胆固醇血症母亲和暂时性高胆固醇血症母亲的胎儿子宫内膜病变明显多于胆固醇血症正常母亲的子宫内膜病变（每个切片分别为758，651 ± 87，449和451，255 ± 37，448 μ m（2）;平均值± SD）（61，862 ± 9，555 μ m（2）; P < 0.00005）。对弓形、胸部和腹部动脉瘤的连续切片进行免疫染色，以确定动脉粥样硬化的标志物：巨噬细胞、载脂蛋白B和两种不同的氧化特异性表位（丙二醛和4-羟基壬烯醛赖氨酸）。在这些标记物中至少有一种显示阳性免疫染色的致动脉粥样硬化部位中，58.6%的已建立病变含有巨噬细胞/泡沫细胞和氧化LDL（OxLDL），17.3%的所有部位仅含有天然LDL，13.3%仅含有OxLDL而不含单核细胞/巨噬细胞。相比之下，只有4.3%的网站包含孤立的单核细胞在天然或氧化LDL的情况下，此外，6.3%的网站包含LDL和巨噬细胞，但很少的氧化特异性表位。这些结果表明，LDL氧化和脂肪条纹的形成已经发生在胎儿发育过程中，这两种现象大大增强了母体高胆固醇血症，事实上，在非常早期的病变LDL和OxLDL经常发现在单核细胞巨噬细胞的情况下，而相反的是罕见的，表明内膜LDL的积累和氧化有助于单核细胞在体内的招聘。
To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo), For this purpose, a systematic assessment: of fatty streak formation tvas carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (It = 27), Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001), In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 mu m(2) per section, respec tively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 mu m(2); P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL), 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL, In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia, The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.