Rutherford Lucy D, Gieseg Steven P
Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand.
Lipids. 2012 Mar;47(3):239-47. doi: 10.1007/s11745-011-3634-1. Epub 2011 Nov 29.
The growth of the necrotic core region within advanced atherosclerotic plaque is thought to be driven by oxidised low density lipoprotein (oxLDL)-induced death of macrophage cells. OxLDL and atherosclerotic plaque are rich in oxysterols, especially 7-ketocholesterol (7KC). As 7KC triggers cell death at physiological concentrations when added directly to the cell culture media, 7KC and other oxysterols have been suggested to be the main cytotoxic agent of oxLDL. We investigated this hypothesis by examining the toxicity of 7KC to monocyte-like U937 cells when incorporated into high-uptake non-toxic acetylated LDL (acLDL). Incorporation of 7KC into acLDL greatly reduced the oxysterol toxicity when compared with an equivalent amount of 7KC added directly to U937 cells. Enrichment of oxLDL with 7KC did not significantly enhance lipoprotein toxicity. OxLDL was highly cytotoxic yet generated only low levels of intracellular 7KC. In comparison, 7KC-acLDL generated high intracellular 7KC concentrations with little loss in cell viability. The data show that when incorporated into lipoprotein, 7KC cytotoxicity is greatly reduced, even though intracellular levels exceed those measured when cells are incubated with oxLDL, which suggests 7KC is not the significant toxic agent within oxLDL.
晚期动脉粥样硬化斑块内坏死核心区域的生长被认为是由氧化型低密度脂蛋白（oxLDL）诱导的巨噬细胞死亡所驱动。OxLDL和动脉粥样硬化斑块富含氧化甾醇，尤其是7-酮胆固醇（7KC）。由于直接添加到细胞培养基中时，7KC在生理浓度下会触发细胞死亡，因此7KC和其他氧化甾醇被认为是oxLDL的主要细胞毒性剂。我们通过研究7KC掺入高摄取无毒乙酰化低密度脂蛋白（acLDL）时对单核细胞样U937细胞的毒性，来验证这一假设。与直接添加到U937细胞中等量的7KC相比，将7KC掺入acLDL可大大降低氧化甾醇的毒性。用7KC富集oxLDL并没有显著增强脂蛋白毒性。OxLDL具有高度细胞毒性，但仅产生低水平的细胞内7KC。相比之下，7KC-acLDL产生高细胞内7KC浓度，而细胞活力几乎没有损失。数据表明，当掺入脂蛋白时，7KC的细胞毒性会大大降低，尽管细胞内水平超过了细胞与oxLDL孵育时测得的水平，这表明7KC不是oxLDL中的主要毒性剂。
