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

ABSTRACT: We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-? dimer (Fib-?D) 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-?D compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-?D formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1? (HIF1?) in pancreata of oxygen-dependent degradation domain-luciferase HIF1? reporter mice. Cerulein also led to induction of genes regulated by HIF1?, including Vegfa and Ero1a, before evidence of Fib-?D 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-?D following administration of cerulein. Feeding mice increased pancreatic expression of HIF1?, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1? has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.

SUBMITTER: Park MJ 

PROVIDER: S-EPMC5927829 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature