Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats

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 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.

β-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy

“…Numerous studies have reported that the gastric mucosa of PHG shows increased susceptibility to injury caused by alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), ischemia/reperfusion and other detrimental factors [5,6]. In addition to the key factor in the development of PHG, portal hypertension, various other elements, including prostaglandins, tumor necrosis factor-α (TNF-α), nitric oxide (NO), oxygen free radicals and transforming growth factor-α (TGF-α), have also been revealed to participate in the pathogenesis of PHG [7][8][9][10]. However, a clear understanding of the molecular basis for this complicated disease is still lacking.…”

Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural history and therapy

“…Rats with PHG exhibited suppression of gastric mucosal COX-1 levels, but exhibited normal COX-2 levels compared to healthy controls [141] . Nonselective COX inhibitors, such as aspirin, decrease PGE2 levels resulting in more apoptosis of cells.…”

“…the pathogenesis of PHG. [141] showed that rats with PHG had increased gastric mucosal apoptosis and decreased mucosal proliferation. Recently, a p53-upregulated modulator of apoptosis (PUMA) was reported markedly induced in gastric mucosa in patients or mouse models of PHG.…”

“…Prostaglandins: Studies in patients or animal models with portal hypertension failed to show significant differences in prostaglandin E2 (PGE2) levels as compared to healthy controls [125,141,[161][162][163] . Low prostaglandin levels significantly decreased gastric perfusion velocity in cirrhotic rats, whereas misoprostol, a PGE2 analogue, significantly increased gastric perfusion in cirrhotic rats as compared to controls [125] .…”

Portal hypertensive gastropathy

“…[32] изучили па-томорфологию ПГГ относительно интенсивности апопто-за эпителиальных клеток. Согласно полученным ими дан-ным, апоптоз эпителиальных клеток в СОЖ играет ключе-вую роль в развитии ПГГ, что было подтверждено другими исследованиями [33].…”