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首页> 外文学位 >Tumor necrosis fractor-alpha-mediated proliferation of vascular smooth muscle cells involves cyclooxygenase.
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Tumor necrosis fractor-alpha-mediated proliferation of vascular smooth muscle cells involves cyclooxygenase.

机译：肿瘤坏死因子-α介导的血管平滑肌细胞增殖涉及环氧合酶。

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摘要

TNF stimulated PGI2 and TXA2 levels in a COX-2-dependent manner. We have previously established that TNF increases COX-2 mRNA and protein expression. The COX-2-selective inhibitors NS-398 and nimesulide and the TXA 2 receptor antagonist BMS 180,291 inhibited TNF-meditated increases in DNA content and cell number by ∼95%. TNF stimulated proliferation of VSMC cells by shortening duration of G1 phase of the cell cycle, which was reflected by the increased cell number in cultures and higher percentage of cells in S and/or G2/M phases of the cycle. This effect was abolished in the presence of NS-398, a selective COX-2 inhibitor, suggesting a COX-2-dependent mechanism contributed to TNF-mediated stimulation of cell proliferation. Addition of TNF did not affect protein to DNA ratio, measured by flow cytometry, suggesting that TNF does not induce VSMC hypertrophy. TNF-mediated modulation of VSMC hyperplasia was further studied in an in vitro model of cell injury, where an area of cells was mechanically removed from a confluent monolayer. Treatment with TNF for 48hr increased proliferation of cells in the injured area by ∼75%, an effect that was prevented in the presence of NS-398 (TNF+NS-398(non-injured area): 5.7+/-1.7; TNF+NS-398(injured-area): 7.4+/-0.8 (%cells S-phases], p<0.05) and effect that was prevented in the presence of NS-398 (TNF(non-injured area): 6.24+/-0.74; TNF(injured-area): 11.08□ 1 [%cells S-phases ], p<0.05). Complete wound healing in the area of injury was observed after addition of TNF for 72 hr; an effect prevented by NS-398. TNF-induced proliferation in the injured area had decreased by 72 hr; possibly related to contact inhibition in the healed area. These data suggest that TNF induces hyperplasia of normal VSMC as well as of VSMC in response to "injury" in vitro. The results obtained from the use of LSC in an in vitro model of injury further supports the contribution of COX-2 to VSMC proliferation induced by TNF.;TNF is known to stimulate both COX-2 and iNOS pathways. The interaction of this pathway was further studied with respect to VMSC proliferation. Indeed, in our system TNF induced a transient increase in VSMC COX-2 and iNOS mRNA accumulation without affecting COX-1 mRNA. COX-2 and iNOS protein expression also increased after challenge with TNF as did TNF-mediated PGI2 and TXA2 production. Pretreatment with aminoguanidine (AG), a selective iNOS inhibitor, attenuated TNF-mediated increases in PGI2 synthesis while TXA2 production and COX-2 protein expression were unaffected. NO donors increased COX-2 protein expression and PGI2 synthesis but had no effect on TXA2 production. Inhibition of NOS activity increased TNF-mediated proliferation of VSMC by approximately 23%, while NO-donors decreased cell number by about 50%. The antiproliferative effect of NO-donors was prevented when COX-2 activity was inhibited with NS-398, a selective COX-2 inhibitor. The data indicated that TNF induces VSMC hyperplasia, but not hypertrophy. Thus, the COX-2 dependent proliferative response of VSMC to TNF was modulated in a NO-dependent manner.
机译：TNF以COX-2依赖性方式刺激PGI2和TXA2水平。我们先前已经确定TNF会增加COX-2 mRNA和蛋白表达。 COX-2选择性抑制剂NS-398和尼美舒利以及TXA 2受体拮抗剂BMS 180,291抑制了TNF介导的DNA含量和细胞数量增加约95％。 TNF通过缩短细胞周期G1期的持续时间来刺激VSMC细胞增殖，这反映在培养物中细胞数量的增加和周期S和/或G2 / M期中较高百分比的细胞中。在选择性COX-2抑制剂NS-398的存在下，该作用被消除，表明COX-2依赖性机制有助于TNF介导的细胞增殖刺激。通过流式细胞仪测量，TNF的添加不影响蛋白质与DNA的比率，表明TNF不会诱导VSMC肥大。在细胞损伤的体外模型中进一步研究了TNF介导的VSMC增生的调节，其中从融合的单层中机械去除细胞区域。 TNF处理48小时可使受损区域的细胞增殖增加约75％，在存在NS-398的情况下（TNF + NS-398（非受伤区域）：5.7 +/- 1.7； TNF + NS-398（受伤区域）：7.4 +/- 0.8（％细胞S期），p <0.05）和在存在NS-398的情况下预防的效果（TNF（非受伤区域）：6.24+ /-0.74; TNF（受伤面积）：11.08＆square; 1 [％细胞S期]，p <0.05）。在加入TNF 72小时后，观察到损伤部位的伤口完全愈合; NS-398。TNF诱导的受伤区域的增殖减少了72小时；可能与愈合区域的接触抑制有关，这些数据表明TNF诱导正常VSMC以及VSMC的增生是由于“损伤”引起的。在损伤的体外模型中使用LSC获得的结果进一步支持了COX-2对TNF诱导的VSMC增殖的贡献；已知TNF可以刺激COX-2和iNOS通路。关于VMSC增殖，对该途径的n进行了进一步研究。实际上，在我们的系统中，TNF诱导了VSMC COX-2和iNOS mRNA积累的短暂增加，而没有影响COX-1 mRNA。 TNF攻击后，COX-2和iNOS蛋白表达也增加，TNF介导的PGI2和TXA2产生也增加。用氨基胍（AG）（一种选择性的iNOS抑制剂）进行的预处理减弱了TNF介导的PGI2合成的增加，而TXA2的产生和COX-2蛋白的表达未受影响。没有供体增加COX-2蛋白表达和PGI2合成，但对TXA2的生产没有影响。 NOS活性的抑制使TNF介导的VSMC增殖增加约23％，而NO供体使细胞数减少约50％。当用选择性COX-2抑制剂NS-398抑制COX-2活性时，就可以防止NO供体的抗增殖作用。数据表明TNF诱导VSMC增生，但不诱导肥大。因此，VSMC对TNF的COX-2依赖性增殖反应以NO依赖性方式被调节。

著录项

  • 作者

    Haider, Asifa.;

  • 作者单位

    New York Medical College.;

  • 授予单位 New York Medical College.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 113 p.
  • 总页数 113
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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