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Pharmacology

Cytoprotection of human endothelial cells from oxidant stress with CDDO derivatives: network analysis of genes responsible for cytoprotection.


PMID 25926128

Abstract

To identify drugs that may reduce the impact of oxidant stress on cell viability. 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. 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). 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.