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Celecoxib induces heme oxygenase-1 expression in macrophages and vascular smooth muscle cells via ROS-dependent signaling pathway

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Abstract

The multiple cytoprotective mechanisms of heme oxygenase (HO)-1 make it a promising therapeutic target. This study investigated whether the selective cyclooxygenase (COX)-2 inhibitor, celecoxib, can upregulate HO-1 expression. Murine J774 macrophages and rat aortic vascular smooth muscle cells (VSMCs) were used to study the effect of celecoxib on HO-1 expression. A signal transduction pathway involving reactive oxygen species (ROS) was also investigated. We found that celecoxib can upregulate HO-1 gene and protein expressions in J774 macrophages and VSMCs. This effect was not diminished by prostaglandin E2 or 15dPGJ2, while it was additive to hypoxia-induced HO-1 expression, suggesting an event independent of COX-2 activity or hypoxia-inducible factor-1α. Moreover, celecoxib activated ERK, p38, Akt, and Nrf2 as well as increased ROS production. All these events contributed to the increase in the expression of HO-1 caused by celecoxib. In this study, we also, for the first time, demonstrated that AMP-activated protein kinase (AMPK) can mediate HO-1 expression via the downstream activation of p38 and Akt. However, the HO-1-inducing actions of celecoxib and hypoxia were not associated with AMPK. This study demonstrates a COX-2-independent action of celecoxib in upregulating HO-1 in macrophages and VSMCs. This action is dependent on ROS, Akt, ERK, p38, and Nrf2 activation. These findings provide new insights into the action mechanism of celecoxib with broad implications for anti-inflammation therapy.

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Abbreviations

15dPGJ2 :

15-Deoxy-delta (12,14)-prostaglandin J2

AICAR:

5-Aminoimidazole-4-carboxamide riboside

AMPK:

AMP-activated protein kinase

HO-1:

Heme oxygenase-1

COX-2:

Cyclooxygenase-2

HIF-1α:

Hypoxia-inducible factor-1α

HUVEC:

Human umbilical vein endothelial cell

l-NAME:

NG-Nitro-l-arginine methyl ester

MAPK:

Mitogen-activated protein kinase

Nrf2:

Nuclear factor (NF)-E2-related factor 2

NSAID:

Nonsteroidal anti-inflammatory drug

ROS:

Reactive oxygen species

VSMC:

Vascular smooth muscle cell

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Acknowledgements

This study was supported by a grant from the National Science Council of Taiwan (NSC97-2314-B-002-017-MY3).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Jang-Shiun Wang, Hao-Cheng Kang & Wan-Wan Lin

  2. Department of Internal Medicine, Tao-Yuan General Hospital, Department of Health, The Executive Yuan, Taoyuan, Taiwan

    Feng-Ming Ho

  3. Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan

    Feng-Ming Ho

  4. Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Kuo-Chin Huang

  5. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Kuo-Chin Huang

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  1. Jang-Shiun Wang
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Correspondence to Kuo-Chin Huang.

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Wang, JS., Ho, FM., Kang, HC. et al. Celecoxib induces heme oxygenase-1 expression in macrophages and vascular smooth muscle cells via ROS-dependent signaling pathway. Naunyn-Schmied Arch Pharmacol 383, 159–168 (2011). https://doi.org/10.1007/s00210-010-0586-6

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  • DOI: https://doi.org/10.1007/s00210-010-0586-6

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