Luoma J S, Strålin P, Marklund S L, Hiltunen T P, Särkioja T, Ylä-Herttuala S
A.I. Virtanen Institute and Department of Medicine, University of Kuopio, Finland.
Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):157-67. doi: 10.1161/01.atv.18.2.157.
Oxidative processes play an important role in atherogenesis. Because superoxide anion and nitric oxide (NO) are important mediators in vascular pathology, we studied the expression of extracellular superoxide dismutase (EC-SOD) and inducible nitric oxide synthase (iNOS) in human and rabbit atherosclerotic lesions by using simultaneous in situ hybridization and immunocytochemistry and EC-SOD enzyme activity measurements. We also analyzed the presence in the arterial wall of oxidized lipoproteins and peroxynitrite-modified proteins as indicators of oxidative damage and possible mediators in vascular pathology. EC-SOD and iNOS mRNA and protein were expressed in smooth muscle cells and macrophages in early and advanced lesions. The expression of both enzymes was especially prominent in macrophages. As measured by enzyme activity, EC-SOD was the major SOD isoenzyme in the arterial wall. EC-SOD activity was higher in highly cellular rabbit lesions but lower in advanced, connective tissue-rich human lesions. Despite the abundant expression of EC-SOD, malondialdehyde-lysine and hydroxynonenal-lysine epitopes characteristic of oxidized lipoproteins and nitrotyrosine residues characteristic of peroxynitrite-modified proteins were detected in iNOS-positive, macrophage-rich lesions, thus implying that malondialdehyde, hydroxynonenal, and peroxynitrite are important mediators of oxidative damage. We conclude that EC-SOD, iNOS, and the balance between NO and superoxide anion play important roles in atherogenesis. EC-SOD and iNOS are highly expressed in lesion macrophages. High EC-SOD expression in the arterial wall may be required not only to prevent deleterious effects of superoxide anion but also to preserve NO activity and prevent peroxynitrite formation. Modulation of arterial EC-SOD and iNOS activities could provide means to protect arteries against atherosclerotic vascular disease.
氧化过程在动脉粥样硬化形成中起重要作用。由于超氧阴离子和一氧化氮（NO）是血管病理过程中的重要介质，我们通过同时使用原位杂交和免疫细胞化学以及测量细胞外超氧化物歧化酶（EC-SOD）的酶活性，研究了人和兔动脉粥样硬化病变中EC-SOD和诱导型一氧化氮合酶（iNOS）的表达。我们还分析了动脉壁中氧化脂蛋白和过氧亚硝酸盐修饰蛋白的存在情况，作为氧化损伤的指标以及血管病理过程中可能的介质。EC-SOD和iNOS的mRNA及蛋白在早期和晚期病变的平滑肌细胞和巨噬细胞中均有表达。这两种酶的表达在巨噬细胞中尤为显著。通过酶活性测定，EC-SOD是动脉壁中的主要超氧化物歧化酶同工酶。在细胞丰富的兔病变中EC-SOD活性较高，但在晚期富含结缔组织的人病变中较低。尽管EC-SOD表达丰富，但在iNOS阳性、富含巨噬细胞的病变中检测到了氧化脂蛋白特有的丙二醛-赖氨酸和羟基壬烯醛-赖氨酸表位以及过氧亚硝酸盐修饰蛋白特有的硝基酪氨酸残基，这意味着丙二醛、羟基壬烯醛和过氧亚硝酸盐是氧化损伤的重要介质。我们得出结论，EC-SOD、iNOS以及NO和超氧阴离子之间的平衡在动脉粥样硬化形成中起重要作用。EC-SOD和iNOS在病变巨噬细胞中高表达。动脉壁中高表达EC-SOD可能不仅是为了防止超氧阴离子的有害作用，也是为了维持NO活性并防止过氧亚硝酸盐的形成。调节动脉EC-SOD和iNOS活性可能为保护动脉免受动脉粥样硬化性血管疾病提供手段。
