HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas
| Autor: | Steven W. Pipe, Diane M. Simeone, M. Bishr Omary, Sapna Iyer, Min-Jung Park, Shufang Gu, Xiang Xue, Juliana Bragazzi Cunha, David S. Moons, John A. Williams, Yatrik M. Shah |
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| Rok vydání: | 2018 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine medicine.medical_specialty Acinar Cells Arginine Article Mice 03 medical and health sciences chemistry.chemical_compound Tissue factor Internal medicine medicine Acinar cell Animals Homeostasis Humans Pancreas Hepatology Chemistry Gastroenterology Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Pancreas Exocrine Vascular endothelial growth factor Disease Models Animal Vascular endothelial growth factor A 030104 developmental biology HIF1A Endocrinology Pancreatitis Acute Disease Acute pancreatitis Ceruletide |
| Zdroj: | Gastroenterology. 154:1630-1634.e3 |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2018.01.037 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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