Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 52, Issue 4, Pages 794-802Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.11.035
Keywords
Carbon monoxide; Inflammation; Vascular cell adhesion molecule; Tumor necrosis factor-alpha
Funding
- German Research Foundation at the Medical Faculty Mannheim of the University of Heidelberg
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Carbon monoxide (CO) abrogates TNF-alpha-mediated inflammatory responses in endothelial cells, yet the underlying mechanism thereof is still elusive. We have previously shown that the anti-inflammatory effect of CO-releasing molecule-3 (CORM-3) is not completely mediated via deactivation of the NF-kappa B pathway. In this study, we sought to explore other potential mechanisms by which CORM-3 downregulates VCAM-1 expression on TNF-alpha-stimulated HUVECs. By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CORM-3. In CORM-3-stimulated HUVECs significant changes in expression were found for genes implicated in the proteasome and porphyrin pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish the effect of CORM-3. Likewise, heme oxygenase-1 inhibitors did not abrogate the ability of CORM-3 to downregulate VCAM-1 expression. Interestingly, CORM-3 inhibited MAPK p38, and the p38 inhibitor SB203580 downregulated VCAM-1 expression. However, downregulation of VCAM-1 by CORM-3 occurred only at concentrations that partly inhibit ATP production and sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. Our results indicate that CORM-3-induced downregulation of VCAM-1 is mediated via p38 inhibition and mitochondrial respiration, whereas the ubiquitin-proteasome system seems not to be involved. (C) 2011 Elsevier Inc. All rights reserved.
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