P179Celecoxib-mediated activation of an AMPK-CREB-Nrf2 dependent pathway: a novel mechanism for endothelial cytoprotection in chronic systemic inflammation

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Abstract

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are important for controlling pain and inflammation. However, concerns remain regarding athero-thrombotic risk. Despite this, clinical evidence suggests that among the COXIBs, celecoxib may have a more positive cardiovascular profile. In addition to targeting cyclo-oxygenase (COX)-2, recent evidence suggests that celecoxib also modulates COX-2-independent cytoprotective signal transduction pathways. We explored the hypothesis that celecoxib may induce anti-oxidant, anti-inflammatory genes in the vascular endothelium via AMP kinase (AMPK) activation, and so protect vascular endothelium against inflammation-mediated injury.

Methods/Results: Human umbilical vein endothelial cells (HUVECs) were studied to investigate the effect of celecoxib on the induction of anti-oxidant enzymes. The results indicated that celecoxib at therapeutically relevant concentrations (1-10μM) induces anti-oxidant genes, including heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and ferritin heavy chain (p<0.05). However, traditional NSAIDs (ibuprofen and naproxen) fail to do this. Dimethyl-celecoxib (DMC), a derivative of celecoxib lacking the COX-2-inhibitory function, reproduced the effects of celecoxib, suggesting that a COX-2-independent signalling pathway is responsible for induction of anti-oxidant enzymes. Celecoxib treatment led to the generation of mitochondrial reactive oxygen species (mROS), and their role in the induction of HO-1 was confirmed by inhibition following pre-treatment of HUVEC with the mROS scavenger MitoTempo (p<0.01). Celecoxib treatment led to phosphorylation of AMPKα(Thr172) and CREB(Ser133) via a linear pathway, and the subsequent nuclear translocation of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The induction of HO-1 by celecoxib was inhibited by siRNA-mediated depletion of AMPKα1, CREB-1, or Nrf2 (p<0.01). Initial functional analysis demonstrated that celecoxib and DMC inhibit TNF-α-induced vascular cell adhesion molecule-1 (VCAM-1) expression (p<0.05), a response not seen with ibuprofen or naproxen.

Conclusion: These data demonstrate the ability of celecoxib to regulate expression of anti-oxidant genes including HO-1 and MnSOD, via a novel endothelial mROS-AMPK-CREB-Nrf2-dependent pathway, and to exert anti-inflammatory cytoprotective effects. We propose that understanding in detail the mechanisms of action of individual anti-inflammatory drugs will inform clinical decisions surrounding the prescription of these drugs, and ultimately lead to the development of more specific and safer alternatives.

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