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Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

¹ University College Dublin, School of Medicine and Medical Science, and Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland

Correspondence and requests for reprints should be addressed to Paul McLoughlin, M.B., Ph.D., University College Dublin, School of Medicine and Medical Sciences, Conway Institute, Belfield, Dublin 4, Ireland. E-mail: paul.mcloughlin{at}ucd.ie

Rationale: 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.

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

Methods: After exposure to environmental hypoxia (10% O₂) 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.

Measurements and Main 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.

Key Words: hypoxia • cAMP response element binding • pulmonary hypertension • transcription factor binding site

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chronic hypoxia causes increased pulmonary vascular resistance and hypertension, changes that are unique to the lung. The mechanisms responsible for the underlying lung-specific changes in gene expression are poorly understood. What This Study Adds to the Field The transcription factors CREB and ATF1 are selectively activated in the hypoxic lung, in particular the pulmonary microvascular endothelium, but not in systemic organs, suggesting a central role for these transcription factors in the pulmonary vascular responses to hypoxia.