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Hypoxia‐inducible Factor‐dependent Production of Profibrotic Mediators by Hypoxic Hepatocytes
Author(s) -
Welch Timothy Paul,
Bustamante Juan,
Moon JeonOk,
Copple Bryan L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1190.5
Subject(s) - downregulation and upregulation , hypoxia (environmental) , hypoxia inducible factors , fibrosis , endocrinology , vascular endothelial growth factor , medicine , mediator , vascular endothelial growth factor a , chemistry , biology , cancer research , biochemistry , organic chemistry , oxygen , vegf receptors , gene
Liver fibrosis is characterized by increased deposition of collagen in the liver during chronic injury. Previous studies have shown that hypoxia‐inducible factor‐1α (HIF‐1α) is a key regulator of profibrotic mediator production during fibrosis. The study goal was to determine whether HIFs are activated in hypoxic hepatocytes and whether they regulate production of profibrotic mediators. Exposure of primary mouse hepatocytes in vitro to either 3% or 1% oxygen (i.e., hypoxia) stimulated nuclear accumulation of HIF‐1α and HIF‐2α proteins. In addition, hypoxia increased expression of proteins implicated in liver fibrosis, including monocyte chemotactic protein‐1 (MCP‐1), vascular endothelial cell growth factor (VEGF), and plasminogen activator inhibitor‐1 (PAI‐1). Hypoxia also increased expression of adrenomedullin‐1 (ADM) and ADM2, proteins implicated in development of hemodynamic abnormalities. Next, to determine whether HIFs are required for upregulation of these mediators by hypoxia, Cre/lox technology was used to delete either HIF‐1α or HIF‐1α from mouse hepatocytes. Results from this study showed that HIFs were required for MCP‐1, VEGF, PAI‐1, ADM, and ADM2 upregulation in hypoxic hepatocytes.