期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 48, 期 8, 页码 1013-1023出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.01.017
关键词
Heme oxygenase-1; Endothelial cells; Inflammation; Redox signaling; Reactive oxygen species; Celecoxib; Cytoprotection; Free radicals
资金
- National Institute for Health Research Biomedical Research Centre
- British Heart Foundation [PG/09/088/28058, FS/10/006/27960] Funding Source: researchfish
Although nonsteroidal anti-inflammatory drugs (NSAIDs) provide important control of pain and inflammation, they have been overshadowed by concerns regarding atherothrombotic complications However, celecoxib seems to have a relatively good cardiovascular profile and may improve endothelial function in coronary heart disease This led us to the hypothesis that celecoxib induces the vasculoprotective enzyme home oxygenase-1 (HO-1) In human umbilical vein and aortic endothelial cells. 24-48 h treatment with celecoxib induced HO-1 mRNA and protein expression and increased HO-1 enzyme activity This effect was not seen with rofecoxib or indomethacin Supplementation of culture medium with iloprost or prostaglandin E-2 failed to reverse celecoxib-mediated HO-1 induction, indicating a cyclooxygenase-independent mechanism Rather, this action of celecoxib involved generation of mitochondria-derived reactive oxygen species. Akt phosphorylation. and nuclear translocation of the transcription factor Nrf2, with N-acetylcysteine. PI-3K antagonist LY290042. and dominant-negative Akt abrogating the effects Furthermore, celecoxib-induced HO-1 was inhibited by dominant-negative Nrf2 The functional significance of HO-1 induction was revealed by celecoxib-mediated inhibition of VCAM-I expression, a response reversed by the HO-1 antagonist zinc protoporphyrin HO-1 induction provides a molecular mechanism for clinical observations indicating relative freedom from atherothrombotic complications in patients taking celecoxib compared to other NSAIDs with comparable anti-inflammatory activity (C) 2010 Elsevier Inc All rights reserved
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