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

Min-Jung Park, Sapna Iyer, Xiang Xue, Juliana Bragazzi Cunha, Gu Shufang, David Moons, Steven W Pipe, John A Williams, Diane M Simeone, Yatrik M Shah, Bishr Omary

Tutkimustuotos: LehtiartikkeliArtikkeliTieteellinenvertaisarvioitu

3 Sitaatiot (Scopus)

Abstrakti

We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-gamma dimer (Fib-gamma 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-gamma D compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-gamma D formation. Cerulein administration resulted in activation and stabilization of hypoxiainducible factor-1 alpha(HIF1 alpha) in pancreata of oxygendependent degradation domain-luciferase HIF1 alpha reporter mice. Cerulein also led to induction of genes regulated by HIF1 alpha, including Vegfa and Ero1 alpha, before evidence of Fib-gamma 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 (Hif1a(Ac-/-)) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-gamma D following administration of cerulein. Feeding mice increased pancreatic expression of HIF1 alpha, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1 alpha has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.
AlkuperäiskieliEi tiedossa
Sivut1630–1634
Sivumäärä8
JulkaisuGastroenterology
Vuosikerta154
Numero6
DOI - pysyväislinkit
TilaJulkaistu - 2018
OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

Keywords

  • Factor VIII
  • mouse model
  • fibrinogen
  • blood clotting

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