Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung.
BACKGROUND
Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation.


OBJECTIVE
To identify transcription factor pathways uniquely activated in the lung in response to hypoxia.


METHODS
After exposure to environmental hypoxia (10% O(2)) for varying periods (3 h to 2 wk), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes the expression of which changed in the hypoxic lung (assessed using microarray analysis) identified potential lung-selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro.


RESULTS
Bioinformatic analysis identified cAMP response element binding (CREB) family members as candidate lung-selective hypoxia-responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and activating transcription factor (ATF)1 and up-regulation of CREB family-responsive genes in the hypoxic lung, but not in other organs. Hypoxia-dependent CREB activation and CREB-responsive gene expression was observed in human primary lung, but not cardiac microvascular endothelial cells.


CONCLUSIONS
These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia, and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia.
Leonard
Martin O
MO
University College Dublin, School of Medicine and Medical Science, and Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
Howell
Katherine
K
Madden
Stephen F
SF
Costello
Christine M
CM
Higgins
Desmond G
DG
Taylor
Cormac T
CT
McLoughlin
Paul
P
D051697:Activating Transcription Factor 1 / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D008168:Lung / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D014655:Vascular Resistance / Q000235:genetics
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors