Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats
Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats
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DOI：
10.1038/cr.2009.97
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发表时间：
2009-08
期刊：
影响因子：
44.1
通讯作者：
Bin Wu;Lixian Zeng;Ying Lin;Zhuofu Wen;Guihua Chen;R. Iwakiri;K. Fujimoto
中科院分区：
文献类型：
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作者：
Bin Wu;Lixian Zeng;Ying Lin;Zhuofu Wen;Guihua Chen;R. Iwakiri;K. Fujimoto
门脉高压胃病是肝硬化的常见并发症，也是肝硬化死亡的主要原因之一。细胞凋亡被广泛认为是一种主动能量依赖性的细胞死亡模式，是与坏死性细胞死亡不同的实体。胃粘膜细胞凋亡是否参与PHT胃病的发生尚不清楚。通过环氧合酶（考克斯）产生的前列腺素（PG）被认为在保护胃肠道粘膜免受损伤和细胞凋亡方面发挥关键作用。然而，考克斯在PHT胃病中的作用仍不清楚。本研究的目的是探讨（1）胃粘膜细胞凋亡是否参与PHT胃病和（2）下调考克斯有助于这种凋亡。在这项研究中，我们发现，胃粘膜细胞凋亡显着增加，而粘膜增殖抑制PHT大鼠。PHT大鼠胃粘膜考克斯1在mRNA和蛋白水平上均受到明显抑制，PGE 2减少。此外，PGE 2治疗抑制PHT大鼠胃粘膜细胞凋亡.然而，假手术大鼠和PHT大鼠之间的胃粘膜考克斯-2水平没有差异。PHT大鼠胃粘膜中肿瘤坏死因子-α（TNF-α）和Fas配体（而非TNF相关凋亡诱导配体）水平升高，活化的caspase-8和caspase-3水平上调。在PHT大鼠中未观察到细胞色素c从线粒体释放到胞质溶胶。我们的数据表明，考克斯-1的下调参与了胃黏膜凋亡通过死亡信号介导的I型细胞死亡在PHT大鼠。
Portal hypertension (PHT) gastropathy is a frequent complication of liver cirrhosis and one of the leading causes of death from cirrhosis. Apoptosis is widely considered to be an active energy-dependent mode of cell death and a distinct entity from necrotic cell death. It is unclear whether gastric mucosal apoptosis is involved in PHT gastropathy. Prostaglandins (PGs) produced through cyclooxygenase (COX) are thought to play a key role in protection of the gastrointestinal mucosa from injury and apoptosis. However, the role of COX in PHT gastropathy is still not clearly understood. The aims of this study were to investigate whether (1) gastric mucosal apoptosis is involved in PHT gastropathy and (2) downregulation of COX contributes to this apoptosis. In this study, we show that gastric mucosal apoptosis was remarkably increased while mucosal proliferation was inhibited in PHT rats. Gastric mucosal COX-1 was significantly suppressed at both the mRNA and protein levels, and PGE 2 was reduced in PHT rats. Further, PGE 2 treatment suppressed gastric mucosal apoptosis in PHT rats. However, gastric mucosal COX-2 levels did not differ between sham-operated rats and PHT rats. Gastric mucosal levels of tumor necrosis factor-α (TNF-α) and Fas ligand, but not TNF-related apoptosis-inducing ligand, were increased, and activated caspase-8 and caspase-3 levels were upregulated in PHT rats. The release of cytochrome c from the mitochondria to the cytosol was not observed in PHT rats. Our data indicate that downregulation of COX-1 is involved in gastric mucosal apoptosis via death signaling-mediated type-I cell death in PHT rats.