Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes
Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes
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DOI：
10.1161/01.res.0000082978.92494.b1
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发表时间：
2003-08-08
影响因子：
20.1
通讯作者：
Twisk, J
中科院分区：
文献类型：
--
作者：
't Hoen, PAC;Van der Lans, CAC;Twisk, J
氧化应激与动脉粥样硬化病变的发展有关。我们评估了 apoE 缺陷小鼠中动脉粥样硬化病变形成的程度与促酶和抗氧化酶的血管表达之间的关系。在正常饮食下，这些小鼠的血清胆固醇水平升高（7.5 至 9.5 倍），并且从 12 周龄开始，各个阶段的动脉粥样硬化病变均出现年龄依赖性自发发展。从主动脉弓和降主动脉提取 RNA，并通过实时 PCR 测量促酶和抗氧化酶的 mRNA 表达。单核细胞/巨噬细胞的局部浸润，通过 CD68 mRNA 的血管表达增加（>10 倍）反映出来，表明主动脉弓比降主动脉更容易受到影响。在病变形成之前的时期（6至12周龄），过氧化氢酶-1以及超氧化物歧化酶、谷胱甘肽过氧化物酶和谷胱甘肽S-转移酶α的各种亚型的表达在主动脉弓中显着增加，但在降主动脉中没有显着增加。这些表达水平比年龄匹配的野生型动物高 1.5 至 5 倍。值得注意的是，病变形成的程度与抗氧化酶的 mRNA 水平之间存在反比关系，随着病变的发展，其中大部分在 12 周后开始下降。相比之下，在疾病过程中，主动脉弓中诱导型一氧化氮合酶的表达增加了 4 倍。我们的结果表明，动脉壁通过刺激抗氧化酶的表达来对致动脉粥样硬化脂蛋白血清水平升高做出反应。观察到的许多这些保护系统表达的协调下降可能会大大加速动脉粥样硬化的发展。
Oxidative stress has been implicated in the development of atherosclerotic lesions. We evaluated the relationship between extent of atherosclerotic lesion formation and vascular expression of pro- and antioxidant enzymes in apoE-deficient mice. On normal chow, these mice showed elevated serum cholesterol levels (7.5- to 9.5-fold), and age-dependent, spontaneous development of all stages of atherosclerotic lesions, starting at the age of 12 weeks. RNA was extracted from the aortic arch and descending aorta, and mRNA expression of pro- and antioxidant enzymes was measured with real-time PCR. Local infiltration of monocytes/ macrophages, reflected by increased vascular expression of CD68 mRNA ( >10-fold), indicated that the arch was more susceptible than the descending aorta. The expression of catalase-1 and various isoforms of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase alpha was significantly increased in the aortic arch, but not in the descending aorta, in the period preceding lesion formation ( age 6 to 12 weeks). These expression levels were 1.5 to 5 times higher than in age-matched wild-type animals. Remarkably, there was an inverse relationship between extent of lesion formation and the mRNA levels of antioxidant enzymes, most of which started to decline after 12 weeks, as lesions developed. In contrast, inducible nitric oxide synthase expression increased 4-fold in the aortic arch over the course of the disease. Our results suggest that the arterial wall responds to increased serum levels of atherogenic lipoproteins by stimulating expression of antioxidant enzymes. The observed co-ordinate decline in expression of many of these protective systems may greatly accelerate the development of atherosclerosis.