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

Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. beta-Arrestins (beta-arrestin-1 and beta-arrestin-2) are well-established mediators of endocytosis of G-protein-coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of beta-arrestin-1 (beta-arrl) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of /9-arrl 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 beta-arr1 and the ER stress/ PUMA signaling pathway were investigated, and the mechanisms of beta-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments, beta-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 fi-orrl significantly aggravated the injury and ER stress/PUMA-mediated apoptosis. beta-arrl limited the activation of p65 to repress INF-alpha-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 beta-arr1 protected against mucosal apoptosis by repressing TNF-alpha-induced iNOS expression via inhibiting the activation of p65. These results indicated that beta-arrl regulated ER stress/ PUMA-induced mucosal epithelial apoptosis through suppression of the TNF-alpha/p65/iNOS signaling pathway activation and that beta-arrl1 is a potential therapeutic target for PHG. (C) 2015 Published by Elsevier Inc.