期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 87, 期 -, 页码 69-83出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.06.004
关键词
Portal hypertensive gastropathy; beta-Arrestin-1; Inducible nitric oxide synthase; Endoplasmic reticulum stress; p53-upregulated modulator of apoptosis; Apoptosis
资金
- Major Projects Incubator Program of National Key Basic Research Program of China [2012CB526700]
- National Natural Science Foundation of China [30971357, 81370511]
- Natural Science Foundation of Guangdong Province [S2011020002348]
- Science and Technology Planning Project of Guangdong Province [2009B060300001]
- International Co-operative Innovative Platform of Guangdong Province Universities and Colleges [gjhz1101]
- Projects of Guangzhou City International Cooperation [2012J5100017]
- Fundamental Research Funds for the Central Universities [13ykjc01]
- 985 Program [82000-3281901]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据