Abstract
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 PGE2 was reduced in PHT rats. Further, PGE2 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.
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Acknowledgements
This work was supported by Grants-in-Aid from the One Hundred Talents Program of Sun Yat-Sen University in China 82000-3171310 (Wu B), and the Ministry of Education, Culture, Sports, Science, and Technology in Japan for Scientific Research 15590656 (Fujimoto K) and 14570478 (Iwakiri R).
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Wu, B., Zeng, L., Lin, Y. et al. Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats. Cell Res 19, 1269–1278 (2009). https://doi.org/10.1038/cr.2009.97
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DOI: https://doi.org/10.1038/cr.2009.97
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