Abstract
Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of the study is to investigate whether PUMA is involved in PHG by mediating ER stress apoptotic signaling. To identify whether PUMA is involved in PHG by mediating ER stress, gastric mucosal injury and apoptosis were studied in both PHG patients and PHG animal models using PUMA knockout (PUMA-KO) and PUMA wild-type (PUMA-WT) mice. The induction of PUMA expression and ER stress signaling were investigated, and the mechanisms of PUMA-mediated apoptosis were analyzed. GES-1 and SGC7901 cell lines were used to further identify whether PUMA-mediated apoptosis was induced by ER stress in vitro. Epithelial apoptosis and PUMA were markedly induced in the gastric mucosa of PHG patients and mouse PHG models. ER stress had a potent role in the induction of PUMA and apoptosis in PHG models, and the apoptosis was obviously attenuated in PUMA-KO mice. Although the targeted deletion of PUMA did not affect ER stress, mitochondrial apoptotic signaling was downregulated in mice. Meanwhile, PUMA knockdown significantly ameliorated ER stress-induced mitochondria-dependent apoptosis in vitro. These results indicate that PUMA mediates ER stress-induced mucosal epithelial apoptosis through the mitochondrial apoptotic pathway in PHG, and that PUMA is a potentially therapeutic target for PHG.
Highlights
Numerous studies have determined that in PHG, the gastric mucosa has an increased susceptibility to injury caused by alcohol, non-steroidal anti-inflammatory drugs (NSAIDs) and other noxious factors.[4,5] the alterations in critical factors accompanying portal hypertension (PHT) such as prostaglandins, tumor necrosis factor-a (TNF-a), nitric oxide (NO), Endothelin-1 and transforming growth factor-a (TGF-a) have been described to participate in the formation of PHG.[6,7,8] the pathogenesis of this disorder has not been fully explored
Real-time PCR data showed that increased p53-upregulated modulator of apoptosis (PUMA) expression was observed in the gastric mucosa of PHG and that PUMA mRNA expression increased 6-fold in the gastric mucosa of PHG patients compared with normal mucosa (Figures 1c and d)
Western blotting analysis showed that the expression of PUMA in PHG was significantly upregulated in the gastric mucosa compared with the normal tissues (Figures 1e and f)
Summary
Numerous studies have determined that in PHG, the gastric mucosa has an increased susceptibility to injury caused by alcohol, non-steroidal anti-inflammatory drugs (NSAIDs) and other noxious factors.[4,5] the alterations in critical factors accompanying portal hypertension (PHT) such as prostaglandins, tumor necrosis factor-a (TNF-a), nitric oxide (NO), Endothelin-1 and transforming growth factor-a (TGF-a) have been described to participate in the formation of PHG.[6,7,8] the pathogenesis of this disorder has not been fully explored. Our previous data demonstrated that gastric mucosal apoptosis was involved in PHG, and many other studies showed that cell death has a pivotal role in the development of PHG.[7,8] Apoptosis has been implicated in tissue damage under a number of pathological conditions.[9,10] The Bcl-2 family proteins include evolutionarily conserved key modulators that mediate apoptosis through the mitochondrial pathway. P53-upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is one of the most potent mediators of p53-dependent and p53-independent apoptosis induced by various stimuli.[11,12] PUMA transduces death signals primarily to the mitochondrial membrane, where it spurs the translocation of Bax and Bak, the release of cytochrome c leads to caspase activation, and the cells die.[13] PUMA knockout (PUMA-KO) in human colon cancer cells or in mice leads to marked attenuation of mitochondrial apoptosis induced by multiple stimuli such as DNA damage, gamma irradiation, kinase inhibition, oncogene activation and endoplasmic reticulum (ER) stress.[14]. The function of PUMA in ER stress-mediated apoptosis has been extensively illustrated in different tissues, whether PUMA is involved in mucosal apoptosis in PHG remains still poorly understood, and whether PUMA induces PHG by mediating ER stress remains unclear
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