Naturally occurring free thiols within beta 2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress-induced cell injury.
β2-Glycoprotein I (β2GPI) is an evolutionary conserved, abundant circulating protein. Although its function remains uncertain, accumulated evidence points toward interactions with endothelial cells and components of the coagulation system, suggesting a regulatory role in vascular biology. Our group has shown that thioredoxin 1 (TRX-1) generates free thiols in β2GPI, a process that may have a regulatory role in platelet adhesion. This report extends these studies and shows for the first time evidence of β2GPI with free thiols in vivo in both multiple human and murine serum samples. To explore how the vascular surface may modulate the redox status of β2GPI, unstimulated human endothelial cells and EAhy926 cells are shown to be capable of amplifying the effect of free thiol generation within β2GPI. Multiple oxidoreductase enzymes, such as endoplasmic reticulum protein 46 (ERp 46) and TRX-1 reductase, in addition to protein disulfide isomerase are secreted on the surface of endothelial cells. Furthermore, one or more of these generated free thiols within β2GPI are also shown to be nitrosylated. Finally, the functional significance of these findings is explored, by showing that free thiol-containing β2GPI has a powerful effect in protecting endothelial cells and EAhy926 cells from oxidative stress-induced cell death.
Ioannou
Yiannis
Y
Department of Immunology, Allergy, and Infectious Diseases, University of New South Wales, Sydney, Australia.
Zhang
Jing-Yun
JY
Passam
Freda H
FH
Rahgozar
Soheila
S
Qi
Jian Cheng
JC
Giannakopoulos
Bill
B
Qi
Miao
M
Yu
Pei
P
Yu
Demin M
DM
Hogg
Philip J
PJ
Krilis
Steven A
SA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000097:blood / Q000378:metabolism*; D013879:Thioredoxins / Q000494:pharmacology; D055815:Young Adult; D053482:beta 2-Glycoprotein I / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D016877:Oxidants; D013438:Sulfhydryl Compounds; D053482:beta 2-Glycoprotein I; D009569:Nitric Oxide; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D019704:Protein Disulfide-Isomerases