Relation of vascular oxidative stress, alpha-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters.
Relation of vascular oxidative stress, alpha-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters.
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血管氧化应激、α-生育酚和高胆固醇血症与仓鼠早期动脉粥样硬化的关系。
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发表时间：
1995
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通讯作者：
B. T. Gill
中科院分区：
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作者：
R. A. Parker;T. Sabrah;M. Cap;B. T. Gill
建立了中度高胆固醇血症（217至271 mg/dL）仓鼠的早期动脉粥样硬化模型，该模型对外源性抗氧化剂高度敏感。该模型的一个关键特征是通过使用缺乏营养抗氧化剂并补充玉米油（10%）和胆固醇（0.2%，0.4%或0.8%）的饮食来提高血管氧化应激。在0.4%胆固醇饮食10周后，平均血浆α-生育酚水平从5.68 +/- 0.30降至1.27 +/- 0.15微克/mL，而通过油红O染色组织学标本的视频显微镜/图像分析测定的主动脉弓中的单核细胞-巨噬细胞泡沫细胞病变从第0周至第60周不可检测增加，第10周时每个样本900 +/- 5400 μ m 2（平均值+/- SEM，n = 36）。α-生育酚或普罗布考给药10周显著抑制LDL离体氧化，并深刻抑制主动脉泡沫细胞形成。然而，抗氧化剂对主动脉病变的影响在较高的血浆胆固醇水平下减弱，尽管离体LDL氧化被有效抑制。当血浆胆固醇水平约为250 mg/dL时，α-生育酚对病变大小的最大效应达到对照值的约36%，半数最大效应的剂量约为10 mg.kg-1. d-1，导致血浆α-生育酚值约为20 μ g/mL。在这些条件下，观察到主动脉病变大小和血浆α-生育酚浓度的线性负相关（n = 68，r =-0.581，P <0.001）。数据表明，LDL氧化是该模型中早期动脉粥样硬化形成的重要组成部分，但表明高脂血症可能超过抗氧化剂的治疗效果。在中度高胆固醇饮食耗尽内源性抗氧化剂的仓鼠中，主动脉病变起始对α-生育酚的高敏感性表明，在动脉粥样硬化的体内模型中，血管氧化应激可以与其他致病因素分离。
A model of early atherosclerosis in hamsters with moderate hypercholesterolemia (217 to 271 mg/dL) was established that was highly responsive to exogenous antioxidants. A key feature of this model was elevation of vascular oxidative stress by use of a diet deficient in nutritional antioxidants and supplemented with corn oil (10%) and cholesterol (0.2%, 0.4%, or 0.8%). After 10 weeks on the 0.4% cholesterol diet, mean plasma alpha-tocopherol levels declined from 5.68 +/- 0.30 to 1.27 +/- 0.15 micrograms/mL, while monocyte-macrophage foam cell lesions in the aortic arch, as assayed by video microscopy/image analysis of oil red O-stained histological specimens, increased from undetectable at week 0 to 60,900 +/- 5400 microns 2 per specimen at week 10 (mean +/- SEM, n = 36). alpha-Tocopherol or probucol administered for 10 weeks markedly suppressed LDL oxidation ex vivo and profoundly inhibited aortic foam cell formation. However, the effects of antioxidants on aortic lesions were attenuated at higher plasma cholesterol levels, although LDL oxidation ex vivo was effectively inhibited. With a plasma cholesterol level at approximately 250 mg/dL, the maximum effect of alpha-tocopherol on lesion size reached approximately 36% of control value, and the dose for half-maximal effect was approximately 10 mg.kg-1.d-1, which resulted in a plasma alpha-tocopherol value of approximately 20 micrograms/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma alpha-tocopherol concentration was observed (n = 68, r = -0.581, P < .001). The data demonstrate that LDL oxidation is a significant component of early atherogenesis in this model but suggest that hyperlipidemia can outweigh the therapeutic effectiveness of antioxidants. The high sensitivity of aortic lesion initiation to alpha-tocopherol in hamsters maintained on moderately hypercholesterolemic diets depleted of endogenous antioxidants demonstrates that vascular oxidative stress can be isolated from other causative factors in an in vivo model of atherosclerosis.