Cytoprotection of human endothelial cells against oxidative stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im): application of systems biology to understand the mechanism of action.
Cellular damage from oxidative stress, in particular following ischemic injury, occurs during heart attack, stroke, or traumatic injury, and is potentially reducible with appropriate drug treatment. We previously reported that caffeic acid phenethyl ester (CAPE), a plant-derived polyphenolic compound, protected human umbilical vein endothelial cells (HUVEC) from menadione-induced oxidative stress and that this cytoprotective effect was correlated with the capacity to induce heme oxygenase-1 (HMOX1) and its protein product, a phase II cytoprotective enzyme. To further improve this cytoprotective effect, we studied a synthetic triterpenoid, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), which is known as a potent phase II enzyme inducer with antitumor and anti-inflammatory activities, and compared it to CAPE. CDDO-Im at 200nM provided more protection to HUVEC against oxidative stress than 20μM CAPE. We explored the mechanism of CDDO-Im cytoprotection with gene expression profiling and pathway analysis and compared to that of CAPE. In addition to potent up-regulation of HMOX1, heat shock proteins (HSP) were also found to be highly induced by CDDO-Im in HUVEC. Pathway analysis results showed that transcription factor Nrf2-mediated oxidative stress response was among the top canonical pathways commonly activated by both CDDO-Im and CAPE. Compared to CAPE, CDDO-Im up-regulated more HSP and some of them to a much higher extent. In addition, CDDO-Im treatment affected Nrf2 pathway more significantly. These findings may provide an explanation why CDDO-Im is a more potent cytoprotectant than CAPE against oxidative stress in HUVEC.
Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, 625 Old Peachtree Road NW, Suwanee, GA 30024-2937, USA. Electronic address: xinyuwa@pcom.edu.
Xinyu
X
Wang
US Army Institute of Surgical Research, Fort Sam Houston, TX 78234, USA; Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, TX 77812, USA.
James A
JA
Bynum
Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, TX 77812, USA.
Solomon
S
Stavchansky
US Army Institute of Surgical Research, Fort Sam Houston, TX 78234, USA. Electronic address: phillip.d.bowman4.vol@mail.mil.
Phillip D
PD
Bowman
D019610:Cytoprotection / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects*; D049490:Systems Biology; D013997:Time Factors
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D009828:Oleanolic Acid
CAPE; CDDO-Im; Cytoprotection; Gene expression analysis; Heme oxygenase-1; Oxidative stress