TY - JOUR
T1 - Diff erential oxidative modifi cation of proteins in MRL +/+ and MRL/lpr mice
T2 - Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response
AU - Wang, Gangduo
AU - Li, Hui
AU - Firoze Khan, M.
N1 - Funding Information:
This work was supported by Grant ES016302 from the National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH.
PY - 2012/12
Y1 - 2012/12
N2 - Even though reactive oxygen species (ROS) have been implicated in SLE pathogenesis, the contributory role of ROS, especially the consequences of oxidative modifi cation of proteins by lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) in eliciting an autoimmune response and disease pathogenesis remains largely unexplored. MRL/lpr mice, a widely used model for SLE, spontaneously develop a condition similar to human SLE, whereas MRL+/+ mice with the same MRL background, show much slower onset of SLE. To assess if the diff erences in the onset of SLE in the two substrains could partly be due to diff erential expression of LPDAs and to provide evidence for the role of LPDA-modifi ed proteins in SLE pathogenesis, we determined the serum levels of MDA-/HNE-protein adducts, anti-MDA-/HNE-protein adduct antibodies, MDA-/HNE-protein adduct specifi c immune complexes, and various autoantibodies in 6-, 12-and 18-week old mice of both substrains. The results show age-related increases in the formation of MDA-/HNE-protein adducts, their corresponding antibodies and MDA-/HNE-specifi c immune complexes, but MRL/lpr mice showed greater and more accelerated response. Interestingly, a highly positive correlation between increased anti-MDA-/HNE-protein adduct antibodies and autoantibodies was observed. More importantly, we further observed that HNE-MSA caused signifi cant inhibition in antinuclear antibodies (ANA) binding to nuclear antigens. These fi ndings suggest that LPDA-modifi ed proteins could be important sources of autoantibodies and CICs in these mice, and thus contribute to autoimmune disease pathogenesis. The observed diff erential responses to LPDAs in MRL/lpr and MRL+/+ mice may, in part, be responsible for accelerated and delayed onset of the disease, respectively.
AB - Even though reactive oxygen species (ROS) have been implicated in SLE pathogenesis, the contributory role of ROS, especially the consequences of oxidative modifi cation of proteins by lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) in eliciting an autoimmune response and disease pathogenesis remains largely unexplored. MRL/lpr mice, a widely used model for SLE, spontaneously develop a condition similar to human SLE, whereas MRL+/+ mice with the same MRL background, show much slower onset of SLE. To assess if the diff erences in the onset of SLE in the two substrains could partly be due to diff erential expression of LPDAs and to provide evidence for the role of LPDA-modifi ed proteins in SLE pathogenesis, we determined the serum levels of MDA-/HNE-protein adducts, anti-MDA-/HNE-protein adduct antibodies, MDA-/HNE-protein adduct specifi c immune complexes, and various autoantibodies in 6-, 12-and 18-week old mice of both substrains. The results show age-related increases in the formation of MDA-/HNE-protein adducts, their corresponding antibodies and MDA-/HNE-specifi c immune complexes, but MRL/lpr mice showed greater and more accelerated response. Interestingly, a highly positive correlation between increased anti-MDA-/HNE-protein adduct antibodies and autoantibodies was observed. More importantly, we further observed that HNE-MSA caused signifi cant inhibition in antinuclear antibodies (ANA) binding to nuclear antigens. These fi ndings suggest that LPDA-modifi ed proteins could be important sources of autoantibodies and CICs in these mice, and thus contribute to autoimmune disease pathogenesis. The observed diff erential responses to LPDAs in MRL/lpr and MRL+/+ mice may, in part, be responsible for accelerated and delayed onset of the disease, respectively.
KW - 4-hydroxynonenal
KW - autoantibodies
KW - lipid peroxidation
KW - malondialdehyde
KW - protein adducts
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U2 - 10.3109/10715762.2012.727209
DO - 10.3109/10715762.2012.727209
M3 - Article
C2 - 22950782
AN - SCOPUS:84868314089
SN - 1071-5762
VL - 46
SP - 1472
EP - 1481
JO - Free Radical Research
JF - Free Radical Research
IS - 12
ER -