title: Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells.
abstract: Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (P<0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (P<0.001). The rate of cell cycle or cell birth rate was increased by 29% (P<0.05) in cells overexpressing HO-1 but decreased by 23% (P<0.05) in cells underexpressing HO-1 compared with control cells. Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing HO-1 but did not decrease cell-cycle progression in cells overexpressing HO-1. High glucose induced p21 and p27 in control cells but not in cells overexpressing HO-1. The addition of tin-mesoporphyrin (SnMP), an inhibitor of HO activity, reversed the HO-1-mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. nader_abraham@nymc.edu
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Kushida
authors.forename: Jack
authors.initials: J
authors.lastname: McClung
authors.forename: Melvin
authors.initials: M
authors.lastname: Weiss
authors.forename: Shuo
authors.initials: S
authors.lastname: Quan
authors.forename: Rocky
authors.initials: R
authors.lastname: Lafaro
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.forename: Michael
authors.initials: M
authors.lastname: Wolin
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D005822:Genetic Vectors; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D008353:Mannitol / Q000494:pharmacology; D008565:Membrane Proteins; D008833:Microcirculation / Q000166:cytology; D012190:Retroviridae / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008353:Mannitol; D014747:Vinblastine; D004247:DNA; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D005947:Glucose