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

• Published in: Clinical and experimental immunology Vol. 176; no. 1; pp. 66 - 77
• Main Authors: Lee, H.‐T., Lin, C.‐S., Lee, C.‐S., Tsai, C.‐Y., Wei, Y.‐H.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2014; Blackwell Science Inc
• Subjects: 8-Hydroxy-2'-Deoxyguanosine; 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG); Adult; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antirheumatic Agents - therapeutic use; anti‐oxidants; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - blood; DNA Damage; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Repair - genetics; DNA, Mitochondrial - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Dosage; Gene Expression Regulation, Enzymologic; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Glutathione Peroxidase GPX1; glycolysis; Glycolysis - genetics; Humans; Leukocytes - drug effects; Leukocytes - metabolism; Leukocytes - pathology; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - metabolism; Male; Middle Aged; Mitochondria - genetics; Mitochondria - metabolism; mitochondrial biogenesis; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Original; Oxidative Stress; Rituximab; RNA, Messenger - genetics; RNA, Messenger - metabolism; Severity of Illness Index; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; systemic lupus erythematosus (SLE); Transcription Factors - genetics; Transcription Factors - metabolism; 8-hydroxy-2′-deoxyguanosine (8-OHdG); systemic lupus erythematosus (SLE); mitochondrial biogenesis; anti-oxidants; glycolysis
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12256

Summary 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.