Reactive aldehyde modification of thioredoxin-1 activates early steps of inflammation and cell adhesion.
Several lines of evidence suggest that an increase in aldehyde-modified proteins is associated with development of atherosclerosis. Acrolein and 4-hydroxynonenal (HNE) are reactive aldehydes generated during active inflammation as a consequence of lipid peroxidation; both react with protein thiols, including thioredoxin-1 (Trx1), a protein recently found to regulate antioxidant function in endothelial cells. The present study examined whether acrolein or HNE modification of Trx1 could potentiate monocyte adhesion to endothelial cells, an early event of atherosclerosis. We examined the function of acrolein and HNE-modified Trx1 in the regulation of the early events of atherosclerosis using cultured aortic endothelial cells as a vascular model system, for in vitro enzymatic assay, and in mass spectrometry analysis. Our data show that acrolein and HNE at 1:1 ratios with Trx1 modified Cys-73 and inhibited activity. In endothelial cells, adducts were detected at concentrations as low as 1 mumol/L including conditions in which there was no detectable change in glutathione. Acrolein and HNE modification of Trx1 was associated with increased production of reactive oxygen species. Microinjection of acrolein- and HNE-modified Trx1 into endothelial cells stimulated monocyte adhesion. Chemical modification of Trx1 by common environmental and endogenously generated reactive aldehydes can contribute to atherosclerosis development by interfering with antioxidant and redox signaling functions of Trx1.
Go
Young-Mi
YM
Department of Medicine (Division of Pulmonary Medicine), Emory University, Atlanta, GA 30322, USA.
Halvey
Patrick J
PJ
Hansen
Jason M
JM
Reed
Matt
M
Pohl
Jan
J
Jones
Dean P
DP
D000171:Acrolein / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000502:physiology*
D000447:Aldehydes; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D000171:Acrolein; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal