Regulation of glutathione by oxidative stress in bovine pulmonary artery endothelial cells.
Glutathione plays important roles as an intracellular antioxidant and in the maintenance of cellular thiol-disulfide balance. In addition, glutathione may regulate cell growth signaling induced by oxidative stress. We previously reported that cellular glutathione is up-regulated by bleomycin in bovine pulmonary artery endothelial cells. The present study examined effects of hydrogen peroxide (H(2)O(2)) on cell growth and glutathione levels. Exogenous addition of H(2)O(2) induced biphasic effects on cell growth; 1 micro M was stimulatory and >10 micro M was inhibitory. However, both growth-promoting and inhibitory levels of H(2)O(2) increased cellular glutathione levels. Whereas 1 micro M H(2)O(2) moderately but significantly increased glutathione, 30 micro M caused a more substantial increase. Like bleomycin, both concentrations of H(2)O(2) activated DNA binding of antioxidant response element (ARE), a regulatory element in the promoter of the gamma-glutamylcysteine synthetase heavy chain subunit, a key regulator of glutathione synthesis. However, only high concentrations of H(2)O(2) activated p44/42 mitogen-activated protein (MAP) kinase. Thus, cellular glutathione is up-regulated by H(2)O(2), perhaps via activating ARE-binding factors in a mechanism independent of MAP kinase. H(2)O(2)-mediated increase in glutathione and activation of ARE binding may play important roles in growth and death of pulmonary artery endothelial cells.
Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, Tupper Research Institute, Department of Medicine, Tufts University, Boston, MA 02111, USA. rday@tufts-nemc.org
Regina M
RM
Day
Yuichiro J
YJ
Suzuki
Barry L
BL
Fanburg
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011651:Pulmonary Artery / Q000166:cytology*; D020218:Response Elements; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
D000975:Antioxidants; D001761:Bleomycin; D004247:DNA; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione