Baird Sarah K, Reid Linzi, Hampton Mark B, Gieseg Steven P
Free Radical Biochemistry Laboratory, School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
Biochim Biophys Acta. 2005 Sep 30;1745(3):361-9. doi: 10.1016/j.bbamcr.2005.07.001.
The atherosclerotic plaque is an inflammatory site where macrophage cells are exposed to cytotoxic oxidised low density lipoprotein (oxLDL). Interferon-gamma released from T-cells results in macrophage synthesis of 7,8-dihydroneopterin which has antioxidant and cytoprotective activity. Using the human derived monocyte-like U937 and THP-1 cell lines, we examined whether 7,8-dihydroneopterin could inhibit the cytotoxic effect of oxLDL. In U937 cells, oxLDL caused a dramatic loss of cellular glutathione and caspase independent cell death associated with phosphatidylserine exposure on the plasma membrane. 7,8-Dihydroneopterin completely blocked the cytotoxic effect of oxLDL. In contrast, oxLDL initiated THP-1 cell apoptosis with reduction in cellular thiols, caspase-3 activation and plasma membrane phosphatidylserine exposure. 7,8-Dihydroneopterin was unable to alter these processes or restore the THP-1 cellular thiol content. 7,8-Dihydroneopterin did provide some protection to both THP-1 cells and U937 cells from AAPH derived peroxyl radicals. The preincubation of oxLDL with 7,8-dihydroneopterin did not reduce cytotoxicity, suggesting that 7,8-dihydroneopterin may be acting in U937 cells by scavenging intracellular oxidants generated by the oxLDL. The data show that muM levels of 7,8-dihydroneopterin may prevent oxLDL mediated cellular death within atherosclerotic plaques.
动脉粥样硬化斑块是一个炎症部位，巨噬细胞在此处会接触到具有细胞毒性的氧化型低密度脂蛋白（oxLDL）。T细胞释放的γ干扰素会导致巨噬细胞合成具有抗氧化和细胞保护活性的7,8-二氢新蝶呤。我们使用源自人类的单核细胞样U937和THP-1细胞系，研究了7,8-二氢新蝶呤是否能抑制oxLDL的细胞毒性作用。在U937细胞中，oxLDL导致细胞内谷胱甘肽大量损失以及与质膜上磷脂酰丝氨酸暴露相关的非半胱天冬酶依赖性细胞死亡。7,8-二氢新蝶呤完全阻断了oxLDL的细胞毒性作用。相比之下，oxLDL引发了THP-1细胞凋亡，伴有细胞内硫醇减少、半胱天冬酶-3激活和质膜磷脂酰丝氨酸暴露。7,8-二氢新蝶呤无法改变这些过程或恢复THP-1细胞内硫醇含量。7,8-二氢新蝶呤确实为THP-1细胞和U937细胞提供了一定程度的保护，使其免受2,2'-偶氮二异丁腈（AAPH）衍生的过氧自由基的损伤。将oxLDL与7,8-二氢新蝶呤预孵育并未降低细胞毒性，这表明7,8-二氢新蝶呤可能通过清除oxLDL产生的细胞内氧化剂而在U937细胞中发挥作用。数据表明，微摩尔水平的7,8-二氢新蝶呤可能预防动脉粥样硬化斑块内oxLDL介导的细胞死亡。
