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Hypoxia activates 15‐ PGDH and its metabolite 15‐ KETE to promote pulmonary artery endothelial cells proliferation via ERK 1/2 signalling
Author(s) -
Ma Cui,
Liu Yun,
Wang Yanyan,
Zhang Chen,
Yao Hongmin,
Ma Jun,
Zhang Lei,
Zhang Dandan,
Shen Tingting,
Zhu Daling
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12594
Subject(s) - hypoxia (environmental) , mapk/erk pathway , microbiology and biotechnology , endothelial stem cell , chemistry , biology , signal transduction , biochemistry , oxygen , organic chemistry , in vitro
Background and Purpose Dysfunction and injury of endothelial cells in the pulmonary artery play critical roles in the hypertension induced by chronic hypoxia. One consequence of hypoxia is increased activity of 15‐hydroxyprostaglandin dehydrogenase (PGDH). Here, we have explored, in detail, the effects of hypoxia on the proliferation of pulmonary artery endothelial cells. Experimental Approach We used bromodeoxyuridine incorporation, cell‐cycle analysis, immunohistochemistry and W estern blot analysis to study the effects of hypoxia, induced 15‐ PGDH ) activity and its product, 15‐keto‐6 Z , 8 Z , 11 Z , 13 E ‐eicosatetraenoic acid (15‐ KETE ), on endothelial cell proliferation. Scratch‐wound and tube formation assays were also used to study migration of endothelial cells. Key Results 15‐ KETE increased DNA synthesis and enhanced the transition from the G 0 / G 1 phase to the S phase in hypoxia. Inhibition of 15‐ PGDH or siRNA for 15‐ PGDH reversed these effects. 15‐ KETE also activated the ERK 1/2 signalling pathway. 15‐ KETE ‐induced cell migration and tube formation were reversed by blocking ERK 1/2, but not the p38 MAPK pathway. Conclusions and Implications Hypoxia‐induced endothelial proliferation and migration, an important underlying mechanism contributing to hypoxic pulmonary vascular remodelling, appears to be mediated by 15‐ PGDH and 15‐ KETE, via the ERK 1/2 signalling pathway.