Premium
Hypoxic‐Induction of Arginase II is Associated with EGFR Activation and EGF Production
Author(s) -
Pool Caitlyn,
Jin Yi,
Chen Bernadette,
Liu Yusen,
Nelin Leif
Publication year - 2015
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.29.1_supplement.661.3
Subject(s) - arginase , hypoxia (environmental) , epidermal growth factor , epidermal growth factor receptor , chemistry , receptor , biology , microbiology and biotechnology , endocrinology , medicine , biochemistry , oxygen , arginine , organic chemistry , amino acid
We have previously shown that hypoxia induces arginase II through epidermal growth factor receptor (EGFR) activation in human pulmonary microvascular endothelial cells (hPMVEC). We hypothesized that hypoxia‐induced EGFR activation occurs via epidermal growth factor (EGF) release. Before studying hPVMEC, HeLa cells were used to dissect cellular mechanisms. Cells were grown in normoxia (21% oxygen) or hypoxia (1% oxygen) for 48 hours and mRNA harvested. RT‐PCR analysis showed substantially higher levels of EGF, EGFR, and arginase II mRNA in the cells incubated in hypoxia than in those incubated in normoxia. Cells were incubated in normoxia or hypoxia for 24 hours, the media harvested and placed on naive cells which were than incubated in normoxia for 48 hours. Cells incubated with hypoxia‐conditioned media had greater arginase II protein levels compared to cells incubated with normoxia‐conditioned media. Cells were then incubated in hypoxia or normoxia for 48 hours with either vehicle or the EGFR kinase inhibitor AG1478 added to the media, and AG1478 treatment prevented hypoxia‐induced arginase II protein expression. Finally, cells were incubated in hypoxia and normoxia for 48 hours with either IgG or an EGFR blocking antibody added to the media, the hypoxia‐induced arginase II expression was substantially lower in the cells incubated with the EGFR blocking antibody than in those incubated with IgG. These findings suggest that hypoxia‐induced arginase II expression may be dependent on EGF‐mediated activation of EGFR. We speculate that the EGFR pathway may be a novel therapeutic target for pulmonary hypertensive disorders associated with hypoxia.