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. 2017 Apr 7:11:1177625017701106.
doi: 10.1177/1177625017701106. eCollection 2017.

Time Course Expression Analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole Induction of Cytoprotection in Human Endothelial Cells

James A Bynum  1   2 , Xinyu Wang  3 , Salomon A Stavchansky  2 , Phillip D Bowman  1
Affiliations

Time Course Expression Analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole Induction of Cytoprotection in Human Endothelial Cells

James A Bynum et al. Gene Regul Syst Bio. .

Abstract

1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a synthetic derivative of oleanolic acid that exhibits antioxidant and anti-inflammatory activity in several animal and in vitro models, has been shown to be beneficial if given after injury. Although induction of heme oxygenase 1 appears to be a major effector of cytoprotection, the mechanism by which the overall effect is mediated is largely unknown. This study evaluated temporal gene expression profiles to better characterize the early transcriptional events and their relationship to the dynamics of the cytoprotective response in human umbilical vein endothelial cells (HUVEC) to CDDO-Im. Time-course gene expression profiling was performed on HUVEC treated with CDDO-Im for 0.5, 1, 3, 6, and 24 hours. More than 10 000 genes were statistically altered in their expression in at least 1 time point across the time course. Large alterations in immediate-early gene expression were readily detectable within 0.5 hour after administration of CDDO-Im.

Keywords: CDDO-IM; Microarray; cytoprotection; time-course gene expression.

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Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Figures

Figure 1.
Figure 1.
Hierarchical agglomerative clustering of genes exhibiting more than an 8-fold statistical alteration in expression (false discovery rate < 10%) based on Pearson correlation coefficient.
Figure 2.
Figure 2.
Immediate-early gene expression levels induced by 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) treatment in human umbilical vein endothelial cells measured with quantitative real-time polymerase chain reaction. JUNB, FOS, DUSP1, and EGR3 expression levels were significantly increased by 30 minutes after CDDO-Im treatment compared with dimethyl sulfoxide (DMSO) control (n = 4; *P < .001). Gene expression levels for this set of genes were back to levels comparable with control (DMSO) by 3 hours.
Figure 3.
Figure 3.
Protein induction by 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) in human umbilical vein endothelial cells by relative Western blot analysis for time points 1, 3, and 6 hours. HMOX1, HSP105, DUSP1, DYRK3, and HSP70 were all compared with dimethyl sulfoxide (DMSO) control (0.1% final concentration). Values are presented as mean values with standard deviations (n = 4; *P < .05).
Figure 4.
Figure 4.
Network of genes constructed by GeneMANIA software on the basis of the functional and biological connectivity of genes. This network highlights the genes induced by 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole after treatment for 0.5 hour and represents the immediate-early gene response. The network is graphically represented as nodes (genes) and edges (the biological relationship between genes). Black nodes represent significantly expressed genes present in the input data submitted to GeneMANIA. Gray nodes represent genes returned by GeneMANIA. The size of each node is proportional to the degree of connectivity within the network, whereas the edge width is proportional to the confidence of the connection.
Figure 5.
Figure 5.
Network of genes constructed by GeneMANIA software on the basis of the functional and biological connectivity of genes. This network highlights the genes induced by 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) after treatment for 3 hours and represents intermediate gene expression response to CDDO-Im. The network is graphically represented as nodes (genes) and edges (the biological relationship between genes). Black nodes represent significantly expressed genes present in the input data submitted to GeneMANIA. Gray nodes represent genes returned by GeneMANIA. The size of each node is proportional to the degree of connectivity within the network, whereas the edge width is proportional to the confidence of the connection.
Figure 6.
Figure 6.
Expression2Kinases network constructed on the basis of the transcription factors, protein-protein interactions, and protein kinases acting within 30 minutes of treatment with 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole . Transcription factor nodes (red), protein-protein interaction nodes (yellow), and kinase (green). Network generated with Cytoscape 3.1.1.
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