Mildly oxidized LDL induces an increased apolipoprotein J paraoxonase ratio
Mildly oxidized LDL induces an increased apolipoprotein J paraoxonase ratio
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DOI：
10.1172/jci119369
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发表时间：
1997-04-15
影响因子：
15.9
通讯作者：
Fogelman, AM
中科院分区：
文献类型：
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作者：
Navab, M;HamaLevy, S;Fogelman, AM
我们研究了轻度氧化的低密度脂蛋白和动脉粥样硬化对两种与高密度脂蛋白相关的蛋白质水平的影响：载脂蛋白J(ApoJ)和对氧磷酶(PON)。在致动脉粥样硬化的饮食中，脂肪条纹易感小鼠C57BL/6J(BL/6)的PON活性降低了52%，apoJ水平增加了2.8倍，而抗脂肪条纹小鼠C3H/HeJ(C3H)则没有。饮食中apoE基因敲除小鼠的血浆PON活性显著降低，apoJ水平显著升高，apoJ/PON比值较对照增加9.2倍。此外，观察到低密度脂蛋白受体基因敲除小鼠的apoJ/PON比率显著增加(超过100倍)，当他们被喂以0.15%的高胆固醇饮食时。将轻度氧化的低密度脂蛋白(但不是天然低密度脂蛋白)注射到饮食正常的BL/6小鼠(但不是C3H小鼠)，可导致PON活性下降59%(P<；0.01)，apoJ水平增加3.6倍(P<；0.01)。当诱导兔急性时相反应或给予致动脉粥样硬化饮食时，肝脏apoJ的mRNA分别增加2.7倍和2.8倍。用轻度氧化的低密度脂蛋白(而不是天然低密度脂蛋白)处理培养的HepG2细胞后，PON的mRNA水平降低(3.0倍)，apoJ的mRNA水平升高(2.0倍)。在冠状动脉造影证实的血脂正常的冠心病患者中(n=14)，没有糖尿病和没有服用降脂药物的患者，总胆固醇/高密度脂蛋白胆固醇比率为3.1+/-0.9，而对照组(n=19)为2.9+/-0.4。这一差异在统计学上并不显著。相比之下，患者组apoJ/PON比值为3.0+/-0.4，对照组为0.72+/-0.2(P<；0.009)。在这些正常血脂患者中的一组(n=5)，PON活性很低(对照组为48+/-6.6U/ml，对照组为98+/-17U/ml；P<；0.009)，尽管高密度脂蛋白水平接近正常，但这些患者的高密度脂蛋白未能防止低密度脂蛋白在共培养的人动脉壁细胞中氧化。我们的结论是：(A)轻度氧化低密度脂蛋白可导致apoJ/PON比值升高，(B)apoJ/PON比值可能比总胆固醇/高密度脂蛋白比值更能预测动脉粥样硬化。
We have examined the effects of mildly oxidized LDL and atherosclerosis on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity decreased by 52%, and apoJ levels increased 2.8-fold in fatty streak susceptible mice, C57BL/6J (BL/6), but not in fatty streak resistant mice, C3H/HeJ (C3H). Plasma PON activity was also significantly decreased, and apoJ levels were markedly increased in apolipoprotein E knockout mice on the chow diet, resulting in a 9.2-fold increase in the apoJ/PON ratio as compared to controls. Furthermore, a dramatic increase in the apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockout mice when they were fed a 0.15%-cholesterol-enriched diet. Injection of mildly oxidized LDL (but not native LDL) into BL/6 mice (but not in C3H mice) on a chow diet resulted in a 59% decrease in PON activity (P < 0.01) and a 3.6-fold increase in apoJ levels (P < 0.01). When an acute phase reaction was induced in rabbits, or the rabbits were placed on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-fold and 2.8-fold, respectively. Treatment of HepG2 cells in culture with mildly oxidized LDL (but not native LDL) resulted in reduced mRNA levels for PON (3.0-fold decrease) and increased mRNA levels for apoJ (2.0-fold increase). In normolipidemic patients with angiographically documented coronary artery disease who did not have diabetes and were not on lipid-lowering medication (n = 14), the total cholesterol/HDL cholesterol ratio was 3.1+/-0.9 as compared to 2.9+/-0.4 in the controls (n = 19). This difference was not statistically significant. In contrast, the apoJ/PON ratio was 3.0+/-0.4 in the patients compared to 0.72+/-0.2 in the controls (P < 0.009). In a subset of these normolipidemic patients (n = 5), the PON activity was low (48+/-6.6 versus 98+/-17 U/ml for controls; P < 0.009), despite similar normal HDL levels, and the HDL from these patients failed to protect against LDL oxidation in co-cultures of human artery wall cells. We conclude that: (a) mildly oxidized LDL can induce an increased apoJ/PON ratio, and (b) the apoJ/PON ratio may prove to be a better predictor of atherosclerosis than the total cholesterol/HDL cholesterol ratio.