Hypoxia activates 15-PGDH and its metabolite 15-KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling.
OBJECTIVE
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.


METHODS
We used bromodeoxyuridine incorporation, cell-cycle analysis, immunohistochemistry and Western blot analysis to study the effects of hypoxia, induced 15-PGDH) activity and its product, 15-keto-6Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15-KETE), on endothelial cell proliferation. Scratch-wound and tube formation assays were also used to study migration of endothelial cells.


RESULTS
15-KETE increased DNA synthesis and enhanced the transition from the G0 /G1 phase to the S phase in hypoxia. Inhibition of 15-PGDH or siRNA for 15-PGDH reversed these effects. 15-KETE also activated the ERK1/2 signalling pathway. 15-KETE-induced cell migration and tube formation were reversed by blocking ERK1/2, but not the p38 MAPK pathway.


CONCLUSIONS
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 ERK1/2 signalling pathway.
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
Cui
C
Ma
Yun
Y
Liu
Yanyan
Y
Wang
Chen
C
Zhang
Hongmin
H
Yao
Jun
J
Ma
Lei
L
Zhang
Dandan
D
Zhang
Tingting
T
Shen
Daling
D
Zhu
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; C054992:15-keto-5,8,11,13-eicosatetraenoic acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
11Z; 13E-eicosatetraenoic acid; 15-hydroxyprostaglandin dehydrogenase; 15-keto-6Z; 8Z; ERK1/2; pulmonary artery endothelial cells; pulmonary vascular remodelling