title: 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.
abstract: Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. β-Arrestins (β-arrestin-1 and β-arrestin-2) are well-established mediators of endocytosis of G-protein-coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of β-arrestin-1 (β-arr1) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of β-arr1 in PHG via its regulation of endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) apoptotic signaling. Gastric mucosal injury and apoptosis were studied in PHG patients and in PHG mouse models. The induction of β-arr1 and the ER stress/PUMA signaling pathway were investigated, and the mechanisms of β-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments. β-arr1 and ER stress/PUMA signaling elements were markedly induced in the gastric mucosa of PHG patients and mouse models. Blockage of ER stress demonstrably attenuated the mucosal apoptosis of PHG, while targeted deletion of β-arr1 significantly aggravated the injury and ER stress/PUMA-mediated apoptosis. β-arr1 limited the activation of p65 to repress TNF-α-induced inducible nitric oxide synthase (iNOS) expression and NO release, which could regulate ER stress/PUMA-mediated mucosal apoptosis in PHG. In vivo and in vitro experiments further demonstrated that β-arr1 protected against mucosal apoptosis by repressing TNF-α-induced iNOS expression via inhibiting the activation of p65. These results indicated that β-arr1 regulated ER stress/PUMA-induced mucosal epithelial apoptosis through suppression of the TNF-α/p65/iNOS signaling pathway activation and that β-arr1 is a potential therapeutic target for PHG.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Siwei
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Leijia
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The No. 2 Hospital of Xiamen, Xiamen, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: binwu001@hotmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019390:Arrestins / Q000096:biosynthesis / Q000235:genetics*; D004705:Endocytosis / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005753:Gastric Mucosa / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006470:Hemorrhage / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: Apoptosis; Endoplasmic reticulum stress; Inducible nitric oxide synthase; Portal hypertensive gastropathy; p53-upregulated modulator of apoptosis; β-Arrestin-1