Diff erential oxidative modifi cation of proteins in MRL +/+ and MRL/lpr mice: Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1472-1481
Number of pages10
JournalFree Radical Research
Volume46
Issue number12
DOIs
StatePublished - Dec 2012

Fingerprint

Inbred MRL lpr Mouse
Autoimmunity
Aldehydes
Lipid Peroxidation
Malondialdehyde
Cations
Lipids
Proteins
Autoantibodies
Antigen-Antibody Complex
Autoimmune Diseases
Antibodies
Reactive Oxygen Species
Nuclear Antigens
4-hydroxy-2-nonenal
Antinuclear Antibodies

Keywords

  • 4-hydroxynonenal
  • autoantibodies
  • lipid peroxidation
  • malondialdehyde
  • protein adducts

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{034f3212ffeb482fa7f2ff3f8d93c4dd,
title = "Diff erential oxidative modifi cation of proteins in MRL +/+ and MRL/lpr mice: Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response",
abstract = "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.",
keywords = "4-hydroxynonenal, autoantibodies, lipid peroxidation, malondialdehyde, protein adducts",
author = "Gangduo Wang and Hui Li and M Khan",
year = "2012",
month = "12",
doi = "10.3109/10715762.2012.727209",
language = "English (US)",
volume = "46",
pages = "1472--1481",
journal = "Free Radical Research",
issn = "1071-5762",
publisher = "Informa Healthcare",
number = "12",

}

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 - Khan, M

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

UR - http://www.scopus.com/inward/record.url?scp=84868314089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868314089&partnerID=8YFLogxK

U2 - 10.3109/10715762.2012.727209

DO - 10.3109/10715762.2012.727209

M3 - Article

C2 - 22950782

AN - SCOPUS:84868314089

VL - 46

SP - 1472

EP - 1481

JO - Free Radical Research

JF - Free Radical Research

SN - 1071-5762

IS - 12

ER -