Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Al-Rashed, F; Calay, D; Lang, M; Thornton, C; Bauer, A; Kiprianos, A; Haskard, D O; Seneviratne, A; Boyle, J J; Schönthal, A H; Wheeler-Jones, C P D; Mason, J C

Abstract

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPK?(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPK? silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000?ppm) or control chow. Functionally, celecoxib inhibited TNF-?-induced NF-?B p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1?-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.

Citation

Al-Rashed, F., Calay, D., Lang, M., Thornton, C., Bauer, A., Kiprianos, A., …Mason, J. C. (2018). Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling. https://doi.org/10.1038/s41598-018-24548-z

• Journal Article Type: Article
• Acceptance Date: Apr 5, 2018
• Publication Date: Apr 19, 2018
• Deposit Date: May 15, 2018
• Publicly Available Date: Nov 21, 2020
• Journal: Scientific Reports (Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Pages: 6271
• DOI: https://doi.org/10.1038/s41598-018-24548-z
• Public URL: https://rvc-repository.worktribe.com/output/1387552