Cytoprotection of human endothelial cells from oxidant stress with CDDO derivatives: network analysis of genes responsible for cytoprotection.
OBJECTIVE
To identify drugs that may reduce the impact of oxidant stress on cell viability.


METHODS
Human umbilical vein endothelial cells were treated with 200 nmol/l CDDO-Im (imidazole) and CDDO-Me (methyl) after exposure to menadione and compared to vehicle-treated cells. Cell viability and cytotoxicity were assessed, and gene expression profiling was performed.


RESULTS
CDDO-Im was significantly more cytoprotective and less cytotoxic (p < 0.001) than CDDO-Me. Although both provided cytoprotection by induction of gene transcription, CDDO-Im induced more genes. In addition to a higher induction of the key cytoprotective gene heme oxygenase-1 (38.9-fold increase for CDDO-Im and 26.5-fold increase for CDDO-Me), CDDO-Im also induced greater expression of heat shock proteins (5.5-fold increase compared to 2.8-fold for CDDO-Me).


CONCLUSIONS
Both compounds showed good induction of heme oxygenase, which largely accounted for their cytoprotective effect. Differences were detected in cytotoxicity at higher doses, indicating that CDDO-Me was more cytotoxic than CDDO-Im. Significant differences were detected in the ability of CDDO-Im and CDDO-Me to affect differential gene transcription. CDDO-Im induced more genes than did CDDO-Me. The source of the differences in gene expression patterns between CDDO-Im and CDDO-Me was not determined but may be important in long-term use of this class of drugs.
US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, Tex., USA.
James A
JA
Bynum
Ashish
A
Rastogi
Salomon A
SA
Stavchansky
Phillip D
PD
Bowman
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D024483:Vitamin K 3 / Q000633:toxicity
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D009828:Oleanolic Acid; D024483:Vitamin K 3; C445068:bardoxolone methyl; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1