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Thioredoxin‐1 mediates hypoxia‐induced pulmonary artery smooth muscle cell proliferation
Author(s) -
Tipple Trent E,
Nelin Viktoria,
Gin Yi,
Rogers Lynette,
Nelin Leif
Publication year - 2012
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.26.1_supplement.873.10
Subject(s) - hypoxia (environmental) , cell growth , luciferase , biology , microbiology and biotechnology , chemistry , medicine , cell culture , transfection , biochemistry , oxygen , genetics , organic chemistry
Pulmonary hypertension (PH) manifests itself in the lungs of both adults and children. The causes of vascular proliferation and remodeling that occur mainly in the pulmonary arterial smooth muscle cells (PASMC) are poorly understood. Hypoxia underlies many forms of PH and alters the redox balance within PASMCs. The aim of this study was to determine the role of the thioredoxin‐ 1 (Trx1) in hypoxia‐induced PASMC proliferation. Human PASMC were exposed to hypoxia (1% O 2 ) or normoxia (21% O 2 ) and Trx1 levels were determined by western blotting. Proliferation studies were done by equally seeding 6 well plates with PASMC, incubating in normoxia or hypoxia for 5 d and counting viable cells using trypan blue exclusion. Our data indicated that hypoxia increases PASMC proliferation. Trx1 levels in hypoxia were significantly greater after 48 and 72 hours of exposure than in PASMC grown in normoxia. Treatment with Trx1‐specific siRNA completely prevented hypoxia‐induced PASMC proliferation. Hypoxia response element (HRE) luciferase reporter studies indicated a 3.5‐fold increase in HRE‐luciferase activity in hypoxia‐exposed PASMCs that was prevented by Trx1 siRNA treatment. Similarly, pharmacological inhibition of Trx1 also prevented hypoxia‐induced increases in PASMC proliferation and HRE‐luciferase activity. Our findings indicate that Trx1 modulates hypoxia‐induced PASMC proliferation, likely through effects on hypoxia‐inducible factor‐mediated pathways. We speculate that Trx1 represents a novel therapeutic target for the vascular remodeling that underlies PH.