Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G1 shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation
Dual functionality of cyclooxygenase-2 as a regulator of tumor necrosis factor-mediated G1 shortening and nitric oxide-mediated inhibition of vascular smooth muscle cell proliferation
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DOI：
10.1161/01.cir.0000085211.97972.2c
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发表时间：
2003-08-26
期刊：
影响因子：
37.8
通讯作者：
Ferreri, NR
中科院分区：
文献类型：
--
作者：
Haider, A;Lee, I;Ferreri, NR
背景--环氧合酶（考克斯）-2参与肿瘤坏死因子（TNF）和血管紧张素II诱导的血管平滑肌细胞（VSMC）增殖。然而，本研究表明，根据主要条件，考克斯-2衍生的前列腺素类也可抑制VSMC增殖。方法和结果-TNF-α通过缩短细胞周期的G（1）期刺激VSMC增殖。选择性考克斯-2抑制剂NS-398可阻断此作用。添加TNF并不影响蛋白质与DNA的比例，通过流式细胞术测量，表明TNF不诱导VSMC肥大。抑制一氧化氮合酶（NOS）活性可减弱TNF介导的前列腺素（PG）I-2合成增加，而血栓素（TX）A（2）生成和考克斯-2蛋白表达不受影响。此外，抑制NOS活性可使TNF介导的增殖增加约23%。因此，NO优先刺激PGI（2）的产生，表明TNF刺激的VSMC产生NO限制了细胞因子增加增殖的能力。NO供体增加了考克斯-2蛋白表达和PGI（2）合成，对TXA（2）的产生没有影响，并使细胞数量减少了50%，表明考克斯-2本身的表达可能不足以支持增殖。结论：TNF对VSMCs的增殖反应具有考克斯-2依赖性，考克斯-2产生的PGI（2）可能参与了NO供体的抗增殖作用。
Background - Cyclooxygenase ( COX)- 2 contributes to vascular smooth muscle cell (VSMC) proliferation induced by tumor necrosis factor (TNF) and angiotensin II. The present study demonstrates, however, that depending on prevailing conditions, COX-2-derived prostanoids may also inhibit VSMC proliferation.Methods and Results - TNF-alpha stimulated proliferation of VSMCs by shortening the G(1) phase of the cell cycle. This effect was abolished by NS-398, a selective COX-2 inhibitor. Addition of TNF did not affect the protein-to-DNA ratio, measured by flow cytometry, suggesting that TNF does not induce VSMC hypertrophy. Inhibition of nitric oxide synthase ( NOS) activity attenuated TNF-mediated increases in prostaglandin (PG) I-2 synthesis, whereas thromboxane (TX) A(2) production and COX-2 protein expression were unaffected. Moreover, inhibition of NOS activity increased TNF-mediated proliferation by approximate to23%. Thus, NO preferentially stimulates PGI(2) production, suggesting that production of NO by VSMCs challenged with TNF limits the ability of the cytokine to increase proliferation. NO donors increased COX-2 protein expression and PGI(2) synthesis, had no effect on TXA(2) production, and decreased cell numbers by 50%, indicating that expression of COX-2 per se might not be sufficient to support proliferation. The effects of NO donors were prevented when COX-2 activity was inhibited with NS-398.Conclusions - The COX-2 - dependent proliferative response of VSMCs to TNF was modulated in an NO-dependent manner, and PGI(2) derived from COX-2 might contribute to the antiproliferative effect of NO donors.