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HIF‐2α regulates hypoxia‐induced arginase II expression through EGFR
Author(s) -
Cui Hongmei,
Liu Yusen,
Chicoine Louis G,
Chen Bernadette,
Nelin Leif D
Publication year - 2013
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.27.1_supplement.724.14
Subject(s) - arginase , hypoxia (environmental) , protein kinase b , gene knockdown , gene silencing , chemistry , mapk/erk pathway , hypoxia inducible factors , transfection , biology , microbiology and biotechnology , signal transduction , apoptosis , biochemistry , oxygen , arginine , gene , organic chemistry , amino acid
To test the hypothesis that arginase II is induced in an oxygen‐dependent manner in human pulmonary microvascular endothelial cells (hPMVEC), cells were incubated in either normoxia (20% O2) or hypoxia (1% O2) for 6 or 24 h, and some of the hypoxic hPMVEC were returned to normoxia or hypoxia for an additional 24 h. The hPMVEC incubated in hypoxia for 24 h produced ~70% less NO than cells incubated in normoxia (p<0.01). Greater HIF‐2α, EGFR, and arginase II protein levels were found in hypoxic hPMVEC than in normoxic cells (p<0.05). Hypoxic hPMVEC returned to normoxia had substantially greater NO production, while arginase II, HIF‐2α, and EGFR protein levels were lower, than in hypoxic hPMVEC (p<0.05). hPMVECs were transfected with siRNA for 48 h to knockdown the expression of HIF‐2α or EGFR. We found that silencing HIF‐2α prevented hypoxia‐induced EGFR and arginase II expression. Conversely, silencing of EGFR also prevented HIF‐2α and arginase II expression, as well as downstream ERK and Akt activation. These results suggest that there is a feedback regulation loop between HIF‐2α and EGFR. Pharmacological inhibition of Akt and MEK1/2 prevented hypoxia‐induced arginase II expression. Thus, arginase II is induced by hypoxia through a pathway mediated by HIF2α, EGFR, ERK, and Akt. We speculate that arginase II regulation may represent a potential therapy for pulmonary hypertension associated with hypoxia.