Celecoxib activates PI-3K/Akt and mitochondrial redox signaling to enhance heme oxygenase-1-mediated anti-inflammatory activity in vascular endothelium

被引：73

作者：

Hamdulay, Shahir S. ^{[1
]}

Wang, Bufei ^{[1
]}

Birdsey, Graeme M. ^{[1
]}

Ali, Faisal ^{[1
]}

Dumont, Odile ^{[1
]}

Evans, Paul C. ^{[1
]}

Haskard, Dorian O. ^{[1
]}

Wheeler-Jones, Caroline P. ^{[2
]}

Mason, Justin C. ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Bywaters Ctr Vasc Inflammat, Natl Heart & Lung Inst, London W12 0NN, England

[2] Univ London Royal Vet Coll, Dept Vet Basic Sci, London, England

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2010年 / 48卷 / 08期

关键词：

Heme oxygenase-1; Endothelial cells; Inflammation; Redox signaling; Reactive oxygen species; Celecoxib; Cytoprotection; Free radicals; CORONARY-ARTERY-DISEASE; COX-2; INHIBITORS; CARDIOVASCULAR RISK; CYCLOOXYGENASE-2; RHEUMATOID-ARTHRITIS; OXIDATIVE DAMAGE; PROTEIN-KINASE; CELLS; DRUGS; EXPRESSION;

D O I：

10.1016/j.freeradbiomed.2010.01.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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

引用

页码：1013 / 1023

页数：11

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