Faculty Collaboration Database

Lethal damage to endothelial cells by oxidized low density lipoprotein: role of selenoperoxidases in cytoprotection against lipid hydroperoxide- and iron-mediated reactions. J Lipid Res 1993 Mar;34(3):479-90

Date

03/01/1993

Pubmed ID

8468531

Scopus ID

2-s2.0-0027409382 (requires institutional sign-in at Scopus site)   139 Citations

Abstract

Oxidized low density lipoprotein (LDLox) is believed to be an important contributor to endothelial cytodamage and atherogenesis. The purpose of this study was to examine the role of glutathione (GSH) and GSH-dependent selenoperoxidases in cytoprotection against the damaging effects of LDLox. When irradiated in the presence of a phthalocyanine sensitizing dye, human LDL accumulated chromatographically detectable and iodometrically measurable lipid hydroperoxides (LOOHs). Photogenerated LDLox caused lethal damage to bovine aortic endothelial (BAE) cells in vitro, as determined by lactate dehydrogenase release and inhibition of thiazolyl blue reduction. When depleted of GSH by buthionine sulfoximine treatment, BAE cells became more sensitive to LDLox. Cells grown in 2% serum/DME-HAM's F-12 medium without added selenium [Se(-) cells] exhibited far lower GSH-peroxidase and phospholipid hydroperoxide GSH-peroxidase activities than selenium-supplemented controls [Se(+) cells], and were much more sensitive to oxidative injury induced by t-butyl hydroperoxide, liposomal cholesterol hydroperoxides, and LDLox. Preincubation of LDLox with GSH and Ebselen (a selenoperoxidase mimetic) resulted in a dramatic reduction in both LOOH content and cytotoxicity. Moreover, treating Se(-) cells themselves with Ebselen substantially restored their resistance to LDLox-induced damage. LDLox toxicity to Se(-) cells was strongly inhibited by desferrioxamine and stimulated by ferric-8-hydroxyquinoline (a lipophilic chelate), indicating that iron is an active participant in oxidative damage. These results demonstrate that the GSH-dependent selenoperoxidase(s) play(s) an important role in cellular defense against oxidized low density lipoprotein, presumably by detoxifying lipid hydroperoxides and thereby preventing their iron-catalyzed decomposition to damaging free radical intermediates.

Author List

Thomas JP, Geiger PG, Girotti AW

Authors

Albert W. Girotti PhD Adjunct Professor in the Biochemistry department at Medical College of Wisconsin
James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antioxidants
Aorta, Thoracic
Azoles
Buthionine Sulfoximine
Cattle
Cell Death
Cells, Cultured
Endothelium, Vascular
Glutathione
Glutathione Peroxidase
Iron
Isoindoles
Lipid Peroxides
Lipoproteins, LDL
Methionine Sulfoximine
Organoselenium Compounds
Oxidation-Reduction
Peroxides
Phenols
Photochemistry
Selenium
tert-Butylhydroperoxide