Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner
Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner
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DOI：
10.1016/j.mad.2008.09.003
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发表时间：
2008-12-01
影响因子：
5.3
通讯作者：
Han, Jeong A.
中科院分区：
文献类型：
--
作者：
Kim, So Ra;Park, Jung Hae;Han, Jeong A.
近年来研究发现，促炎基因如环氧合酶-2（cyclooxygenase-2，考克斯-2）在衰老过程中起关键作用。然而，考克斯-2的促炎活性是否参与衰老过程以及考克斯-2抑制剂是否预防衰老仍不清楚。因此，我们研究了考克斯-2抑制剂对人皮肤成纤维细胞（HDF）细胞衰老模型中衰老的影响。虽然观察到考克斯-2的催化活性在衰老过程中增加，但我们发现，在所研究的三种选择性考克斯-2抑制剂中，只有NS-398抑制衰老，而塞来昔布和尼美舒利加速衰老。非选择性考克斯抑制剂包括阿司匹林、布洛芬和氟比洛芬加速衰老。选择性考克斯-2抑制剂的衰老调节作用与细胞活性氧水平、NF-κ B活性或p53和p21蛋白水平无关。相反，我们发现选择性考克斯-2抑制剂在转录水平上调节caveolin-1的表达，这与抑制剂对衰老的影响密切相关。总之，这些结果表明，考克斯-2催化活性不介导HDF衰老，选择性考克斯-2抑制剂通过催化活性非依赖性机制调节HDF衰老。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
It has been recently proposed that pro-inflammatory genes Such as cyclooxygenase-2 (COX-2) play a key role in the aging process. However, it remains Unclear whether the pro-inflammatory activity of COX-2 is involved in the aging process and whether COX-2 inhibitors prevent aging. We therefore examined the effect of COX-2 inhibitors on aging in the cellular senescence model of human dermal fibroblasts (HDFs). While the catalytic activity of COX-2 was observed to increase in the senescence process, we found that among three selective COX-2 inhibitors studied, only NS-398 inhibited the senescence whereas celecoxib and nimesulide accelerated the senescence. Non-selective COX inhibitors including aspirin, ibuprofen and flurbiprofen accelerated the senescence. The senescence-regulating effect of selective COX-2 inhibitors had no correlation with cellular reactive oxygen species levels, NF-kappa B activities or protein levels of p53 and p21. We instead found that selective COX-2 inhibitors regulate caveolin-1 expression at transcriptional levels, which was closely associated with the inhibitors' effect on the senescence. Collectively, these results suggest that COX-2 catalytic activity does not mediate HDF senescence and that selective COX-2 inhibitors modulate HDF senescence by a catalytic activity-independent mechanism. (C) 2008 Elsevier Ireland Ltd. All rights reserved.