Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension.
Pulmonary hypoxia is a common complication of chronic lung diseases leading to the development of pulmonary hypertension. The underlying sustained increase in vascular resistance in hypoxia is a response unique to the lung. Thus we hypothesized that there are genes for which expression is altered selectively in the lung in response to alveolar hypoxia. Using a novel subtractive array strategy, we compared gene responses to hypoxia in primary human pulmonary microvascular endothelial cells (HMVEC-L) with those in cardiac microvascular endothelium and identified 90 genes (forming 9 clusters) differentially regulated in the lung endothelium. From one cluster, we confirmed that the bone morphogenetic protein (BMP) antagonist, gremlin 1, was upregulated in the hypoxic murine lung in vivo but was unchanged in five systemic organs. We also demonstrated that gremlin protein was significantly increased by hypoxia in vivo and inhibited HMVEC-L responses to BMP stimulation in vitro. Furthermore, significant upregulation of gremlin was measured in lungs of patients with pulmonary hypertensive disease. From a second cluster, we showed that CXC receptor 7, a receptor for the proangiogenic chemokine CXCL12, was selectively upregulated in the hypoxic lung in vivo, confirming that our subtractive strategy had successfully identified a second lung-selective hypoxia-responsive gene. We conclude that hypoxia, typical of that encountered in pulmonary disease, causes lung-specific alterations in gene expression. This gives new insights into the mechanisms of pulmonary hypertension and vascular loss in chronic lung disease and identifies gremlin 1 as a potentially important mediator of vascular changes in hypoxic pulmonary hypertension.
Costello
Christine M
CM
School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Sciences, University College Dublin, Dublin, Ireland. christine.costello@ucd.ie
Howell
Katherine
K
Cahill
Edwina
E
McBryan
Jean
J
Konigshoff
Melanie
M
Eickelberg
Oliver
O
Gaine
Sean
S
Martin
Finian
F
McLoughlin
Paul
P
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D051379:Mice; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000378:metabolism*; D054387:Receptors, CXCR / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000098:blood supply / Q000378:metabolism*; D016207:Cytokines
D019485:Bone Morphogenetic Proteins; D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; D054387:Receptors, CXCR; D043562:Receptors, G-Protein-Coupled; C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; C486399:GREM1 protein, human; C113178:Grem1 protein, mouse; D016207:Cytokines