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

Abstract

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 200 nM provided more protection to HUVEC against oxidative stress than 20 M 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.

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Document Details

Document Type
Technical Report
Publication Date
Apr 03, 2014
Accession Number
ADA620237

Entities

People

  • James A. Bynum
  • Phillip D. Bowman
  • Solomon Stavchansky
  • Xinyu Wang

Organizations

  • United States Army Institute of Surgical Research

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Cardiovascular Diseases
  • Cell Physiological Processes
  • Cells
  • Computational Biology
  • Data Sets
  • Endothelial Cells
  • Free Radicals
  • Gene Expression
  • Health Services
  • Imidazoles
  • Microarray Analysis
  • Neoplasms
  • Oxidative Stress
  • Proteins
  • Systems Biology
  • Transcription Factors
  • Vascular Diseases

Fields of Study

  • Biology

Readers

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