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首页> 美国卫生研究院文献>Clinical and Experimental Immunology >Increased 8-hydroxy-2′-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1 anti-oxidant enzymes mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus
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Increased 8-hydroxy-2′-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1 anti-oxidant enzymes mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus

机译：系统性红斑狼疮患者血浆中8-羟基-2-脱氧鸟苷的增加和人类8-氧鸟嘌呤DNA糖基化酶1抗氧化酶线粒体生物发生相关蛋白和糖酵解酶的mRNA表达降低

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We measured plasma levels of the oxidative DNA damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) and leucocyte mRNA expression levels of the genes encoding the 8-OHdG repair enzyme human 8-oxoguanine DNA glycosylase 1 (hOGG1), the anti-oxidant enzymes copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase-1 (GPx-1), GPx-4, glutathione reductase (GR) and glutathione synthetase (GS), the mitochondrial biogenesis-related proteins mtDNA-encoded ND 1 polypeptide (ND1), ND6, ATPase 6, mitochondrial transcription factor A (Tfam), nuclear respiratory factor 1(NRF-1), pyruvate dehydrogenase E1 component alpha subunit (PDHA1), pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) and hypoxia inducible factor-1α (HIF-1α) and the glycolytic enzymes hexokinase-II (HK-II), glucose 6-phosphate isomerase (GPI), phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase A (LDHa). We analysed their relevance to oxidative damage in 85 systemic lupus erythematosus (SLE) patients, four complicated SLE patients undergoing rituximab treatment and 45 healthy individuals. SLE patients had higher plasma 8-OHdG levels (P < 0·01) but lower leucocyte expression of the genes encoding hOGG1(P < 0·01), anti-oxidant enzymes (P < 0·05), mitochondrial biogenesis-related proteins (P < 0·05) and glycolytic enzymes (P < 0·05) than healthy individuals. The increase in plasma 8-OHdG was correlated positively with the elevation of leucocyte expression of the genes encoding hOGG1 (P < 0·05), anti-oxidant enzymes (P < 0·05), several mitochondrial biogenesis-related proteins (P < 0·05) and glycolytic enzymes (P < 0·05) in lupus patients. The patients, whose leucocyte mtDNA harboured D310 heteroplasmy, exhibited a positive correlation between the mtDNA copy number and expression of ND1, ND6 and ATPase 6 (P < 0·05) and a negative correlation between mtDNA copy number and systemic lupus erythematosus disease activity index (SLEDAI) (P < 0·05), as well as plasma 8-OHdG (P < 0·05). In particular, four complicated SLE patients with increased expression of the genes encoding the anti-oxidant enzymes, GAPDH, Tfam and PDHA1, experienced better therapeutic outcomes after rituximab therapy. In conclusion, higher oxidative damage with suboptimal increases in DNA repair, anti-oxidant capacity, mitochondrial biogenesis and glucose metabolism may be implicated in SLE deterioration, and this impairment might be improved by targeted biological therapy.
机译：我们测量了氧化性DNA损伤标记物8-hydroxy-2'-deoxyguanosine（8-OHdG）的血浆水平和编码8-OHdG修复酶人类8-oxoguanine DNA糖基化酶1（hOGG1）的基因的白细胞mRNA表达水平，抗氧化酶铜/锌超氧化物歧化酶（Cu / ZnSOD），锰超氧化物歧化酶（MnSOD），过氧化氢酶，谷胱甘肽过氧化物酶-1（GPx-1），GPx-4，谷胱甘肽还原酶（GR）和谷胱甘肽合成酶（GS），线粒体生物发生相关蛋白mtDNA编码的ND 1多肽（ND1），ND6，ATPase 6，线粒体转录因子A（Tfam），核呼吸因子1（NRF-1），丙酮酸脱氢酶E1组分α亚基（PDHA1），丙酮酸脱氢酶激酶同工酶1（PDK-1）和缺氧诱导因子1α（HIF-1α）以及糖酵解酶己糖激酶II（HK-II），葡萄糖6磷酸异构酶（GPI），果糖磷酸激酶（PFK），甘油醛3-磷酸脱氢酶（GAPDH）和乳酸脱氢酶A（LDHa）。我们分析了它们与85例系统性红斑狼疮（SLE）患者，四名接受利妥昔单抗治疗的复杂SLE患者和45名健康个体的氧化损伤的相关性。 SLE患者血浆中的8-OHdG水平较高（P <0·01），但编码hOGG1（P <0·01），抗氧化酶（P <0·05），线粒体生物发生相关蛋白的基因的白细胞表达较低（P <0·05）和糖酵解酶（P <0·05）高于健康个体。血浆8-OHdG的增加与编码hOGG1（P <0·05），抗氧化酶（P <0·05），几种线粒体生物发生相关蛋白（P < 0·05）和狼疮患者的糖酵解酶（P <0·05）。白细胞mtDNA带有D310异质性的患者，其mtDNA拷贝数与ND1，ND6和ATPase 6表达呈正相关（P <0·05），而mtDNA拷贝数与系统性红斑狼疮疾病活动指数呈负相关（SLEDAI）（P <0·05），以及血浆8-OHdG（P <0·05）。尤其是，四名复杂的SLE患者，其抗氧化酶GAPDH，Tfam和PDHA1的编码基因表达增加，利妥昔单抗治疗后的治疗效果更好。总之，较高的氧化损伤与DNA修复，抗氧化能力，线粒体生物发生和葡萄糖代谢的最佳降低有关，可能与SLE恶化有关，并且有针对性的生物疗法可以改善这种损害。

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