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Hypoxia activates NFκB and HIF1α in an erythrocyte‐dependent manner in lung endothelium
Author(s) -
Huertas Alice,
Das Shonit R.,
Emin Memet,
Inamdar Nilufar M.,
Rifkind Joseph M.,
Bhattacharya Sunita,
Bhattacharya Jahar
Publication year - 2010
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.24.1_supplement.796.5
Subject(s) - hypoxia (environmental) , hif1a , endothelium , hypoxic pulmonary vasoconstriction , biology , lung , collagenase , inflammation , signal transduction , perfusion , endothelial stem cell , microbiology and biotechnology , immunology , chemistry , medicine , biochemistry , endocrinology , angiogenesis , in vitro , enzyme , cancer research , oxygen , organic chemistry
Although hypoxia causes lung inflammation, the initiating mechanisms are not understood. We reported that in hypoxic lungs, erythrocyte‐derived H2O2 diffuses to capillaries (Kiefmann, 2008). To determine endothelial signaling, we ventilated isolated mouse lungs, perfused with erythrocyte‐containing (ERY+) or ‐free (ERY−) buffer, for 4 hours with 21 (normoxia) or 8% (hypoxia) O2. Then we infused chilled collagenase and trypsin in the pulmonary artery to obtain freshly isolated lung endothelial cells (FLEC) (Yiming, 2008). For hypoxia alone, immunoblots of FLEC nuclear fractions revealed bands for NF?B subunit p65 and HIF1a. These responses were abrogated both for ERY− perfusion and ERY+ perfusion containing catalase, indicating that the NF?B and HIF1? pathways were activated by erythrocyte‐ and H2O2‐dependent mechanisms. In mice expressing endothelial‐specific, inactive I?Ba, exposure to 8% O2 for 4 hours failed to induce nuclear translocation of p65 or HIF1a, indicating that NF?B is an upstream regulator of HIF1a. Taken together, our findings are the first evidence that in hypoxia, erythrocyte‐derived H2O2 triggers NF?B and HIF1a activation in endothelial cells. Further, our data affirm that hypoxia‐induced endothelial HIF1a stabilization is NF?B dependent. These signaling pathways are likely to be important in the induction of hypoxic lung inflammation. (Support: HL69514, HL36024).