Björkerud B, Björkerud S
Department of Pathology, Institute of Laboratory Medicine, Göteborg University, Sweden.
Arterioscler Thromb Vasc Biol. 1996 Mar;16(3):416-24. doi: 10.1161/01.atv.16.3.416.
The inhibition of experimental atherosclerosis by antioxidants and the presence of oxidized LDL (oxLDL) in atherosclerotic lesions indicate that oxLDL may play what is perhaps a primary role in atherogenesis. LDL promotes the growth of arterial smooth muscle cells (SMCs), and oxLDL has cytotoxic effects. Since excessive intimal growth alternating with necrosis is typical of atherosclerotic lesions, we wondered whether these extreme changes in the lesions could be related to the extreme effects of LDL and oxLDL on cells. We therefore examined the effects of increasing LDL oxidation on its capacity to induce cell growth or cell death and whether the latter could be due to apoptosis. Cells of the types present in the atherosclerotic artery used, ie, SMCs (human arterial), macrophages (human macrophage-like cell line THP-1), and human fibroblasts. Growth was evaluated by measuring the synthesis of DNA and culture size (MTT method) and apoptosis by using the in situ labeling of internucleosomally degraded DNA and, in the case of SMCs, the appearance of chromatin condensation. The oxidation of LDL was by UV or Fe ions. Shortly oxidized LDL had a markedly increased growth-promoting effect on all cell types. With prolonged exposure to UV, but not to Fe, LDL became increasingly cytotoxic, and this toxicity was paralleled by the appearance of apoptosis in all cell types. After prolonged UV treatment, low-molecular-weight material from the partially degraded LDL was responsible for the induction of apoptosis. The dual effect of oxLDL, ie, its strong growth-promoting effect or the induction of cell death by apoptosis, depending on the degree of change by oxidation, is compatible with the notion that oxLDL plays a role not only in atherogenesis but also more extensively in the development of the structure typical of the atherosclerotic lesion, with focal excessive growth alternating with necrosis.
抗氧化剂对实验性动脉粥样硬化的抑制作用以及动脉粥样硬化病变中氧化型低密度脂蛋白（oxLDL）的存在表明，oxLDL可能在动脉粥样硬化形成过程中发挥着或许是主要的作用。低密度脂蛋白（LDL）促进动脉平滑肌细胞（SMC）的生长，而oxLDL具有细胞毒性作用。由于内膜过度生长与坏死交替出现是动脉粥样硬化病变的典型特征，我们想知道病变中的这些极端变化是否可能与LDL和oxLDL对细胞的极端作用有关。因此，我们研究了增加LDL氧化对其诱导细胞生长或细胞死亡能力的影响，以及后者是否可能是由于细胞凋亡所致。使用的动脉粥样硬化动脉中存在的细胞类型，即SMC（人动脉）、巨噬细胞（人巨噬细胞样细胞系THP-1）和人成纤维细胞。通过测量DNA合成和培养物大小（MTT法）评估生长情况，并通过对核小体间降解DNA进行原位标记以及对于SMC通过观察染色质凝聚的出现来评估细胞凋亡。LDL的氧化通过紫外线或铁离子进行。短期氧化的LDL对所有细胞类型均具有显著增强的促生长作用。随着紫外线照射时间延长，但铁离子处理则不然，LDL的细胞毒性越来越大，并且这种毒性与所有细胞类型中细胞凋亡的出现平行。经过长时间紫外线处理后，部分降解的LDL中的低分子量物质可诱导细胞凋亡。oxLDL的双重作用，即其强大的促生长作用或通过细胞凋亡诱导细胞死亡，取决于氧化程度的变化，这与oxLDL不仅在动脉粥样硬化形成中起作用，而且在动脉粥样硬化病变典型结构的发展中更广泛地起作用的观点相符，即局部过度生长与坏死交替出现。
