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 AMPKα^(Thr172) and CREB-1^(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα 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-α-induced NF-κB 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-1β-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.

中文翻译：

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塞来昔布通过不依赖COX-2的AMPK-CREB-Nrf2信号激活在血管内皮中发挥保护作用。

尽管仍然担心由环加氧酶（COX）-2-选择性抑制剂引起的动脉粥样硬化血栓形成风险，但最近的数据暗示罗非考昔，而塞来昔布似乎等同于NSAIDs萘普生和布洛芬。我们调查了塞来昔布激活AMP激酶（AMPK）信号增强血管内皮保护的假设。在人的动脉和静脉内皮细胞（EC）中，与布洛芬和萘普生相反，塞来昔布诱导了保护性蛋白血红素加氧酶-1（HO-1）。缺乏COX-2抑制作用的塞来昔布衍生物2,5-二甲基-celecoxib（DMC）也上调了HO-1，暗示了与COX-2无关的机制。塞来昔布激活的AMPKα ^（Thr172）和CREB-1 ^（Ser133）磷酸化导致Nrf2核易位。重要的是，布洛芬或萘普生未重现这些反应，而AMPKα沉默则废除了塞来昔布介导的CREB和Nrf2活化。此外，塞来昔布通过相同途径诱导H-铁蛋白，并在喂食塞来昔布（1000 ppm）或对照食物的小鼠的主动脉内皮中增加了HO-1和H-铁蛋白。在功能上，塞来昔布抑制TNF-α诱导的NF-κBp65 ^（Ser536）通过激活AMPK进行磷酸化。这通过诱导HO-1减弱了VCAM-1的上调，HO-1的诱导是DMC复制的，但不是布洛芬或萘普生。同样，塞来昔布可阻止IL-1β介导的IL-6诱导。塞来昔布通过AMPK-CREB-Nrf2信号增强血管保护作用，该机制可减轻开具塞来昔布患者的心血管风险。了解NSAID异质性和独立于COX-2的信号传导将最终导致更安全的抗炎药。