Aminothiols protect endothelial cell proliferation against inhibition by lipopolysaccharide.
Lipopolysaccharide (LPS) is a primary agent of sepsis that damages the vascular endothelium. Endothelial cell proliferation is key to the repair of damaged endothelium, and drugs that counteract the antiproliferative impact of LPS on endothelial cells should be beneficial. Because LPS exerts much of its cytotoxicity by generating reactive oxygen and nitrogen intermediates, it would be helpful to know whether therapeutic antioxidant thiols maintain cell proliferation in injured endothelium. In this study, it was found that LPS inhibited bovine aortic endothelial cell proliferation by inducing apoptosis and by decreasing DNA synthesis. Because of its benefit to irradiated endothelial cells, we then treated the cells with a radio- and chemoprotective aminothiol, WR-1065 ([N-2-mecaptoethyl]-1-3-diaminopropane, the active form of Amifostine/Ethyol). WR-1065 attenuated the inhibition of DNA synthesis caused by LPS exposure. The disulfide of WR-1065, WR-33278, was tested and shown to both promote DNA synthesis and inhibit apoptosis. The effectiveness of the disulfide suggests that the reduction of cytotoxicity does not necessarily result from the scavenging of free radicals. These findings demonstrate a novel role for aminothiols in promoting DNA synthesis and lowering apoptosis in endothelium injured with LPS.
Drab-Weiss
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Department of Medicine, Rush University Medical College, Chicago, Illinois 60612, USA.
Hansra
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Blazek
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Rubin
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DB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000293:injuries; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008624:Mercaptoethylamines / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy / Q000473:pathology
D008070:Lipopolysaccharides; D008624:Mercaptoethylamines; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004247:DNA