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HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

Abstract：

:We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-γ dimer (Fib-γD) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-γD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-γD formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1α (HIF1α) in pancreata of oxygen-dependent degradation domain-luciferase HIF1α reporter mice. Cerulein also led to induction of genes regulated by HIF1α, including Vegfa and Ero1a, before evidence of Fib-γD deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1aAc-/-) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-γD following administration of cerulein. Feeding mice increased pancreatic expression of HIF1α, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1α has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Park MJ,Iyer S,Xue X,Bragazzi Cunha J,Gu S,Moons D,Pipe SW,Williams JA,Simeone DM,Shah YM,Omary MB

doi

10.1053/j.gastro.2018.01.037

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1630-1634.e3

issue

6

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(18)30102-1

journal_volume

154

pub_type

杂志文章

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