Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension

被引:64
作者
Costello, Christine M. [1 ]
Howell, Katherine [1 ]
Cahill, Edwina [1 ]
McBryan, Jean [2 ]
Konigshoff, Melanie [3 ]
Eickelberg, Oliver [3 ]
Gaine, Sean [4 ]
Martin, Finian [2 ]
McLoughlin, Paul [1 ]
机构
[1] Univ Coll Dublin, Sch Med & Med Sci, UCD Conway Inst Biomol & Biomed Sci, Dublin 2, Ireland
[2] Univ Coll Dublin, Sch Biomol & Biomed Sci, UCD Conway Inst Biomol & Biomed Sci, Dublin 2, Ireland
[3] Univ Giessen, Lung Ctr, Dept Med 2, Giessen, Germany
[4] Univ Coll Dublin, Mater Misericordiae Univ Hosp, Dept Resp Med, Dublin 2, Ireland
关键词
pulmonary endothelium; gremlin; 1; CXC receptor 7; angiogenesis;
D O I
10.1152/ajplung.00358.2007
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:L272 / L284
页数:13
相关论文
共 59 条
[1]   Endothelium-derived mediators and hypoxic pulmonary vasoconstriction [J].
Aaronson, PI ;
Robertson, TP ;
Ward, JPT .
RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, 2002, 132 (01) :107-120
[2]   Developmental expression of mouse Follistatin-like 1 (Fstl1):: Dynamic regulation during organogenesis of the kidney and lung [J].
Adams, Derek ;
Larman, Barry ;
Oxburgh, Leif .
GENE EXPRESSION PATTERNS, 2007, 7 (04) :491-500
[3]   The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes [J].
Balabanian, K ;
Lagane, B ;
Infantino, S ;
Chow, KYC ;
Harriague, J ;
Moepps, B ;
Arenzana-Seisdedos, F ;
Thelen, M ;
Bachelerie, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (42) :35760-35766
[4]   Antibody-mediated lung endothelium targeting: in vivo model on primates [J].
Balyasnikova, IV ;
Yeomans, DC ;
McDonald, TB ;
Danilov, SM .
GENE THERAPY, 2002, 9 (04) :282-290
[5]   Biochemical and morphological changes in endothelial cells in response to hypoxic interstitial edema [J].
Botto, L ;
Beretta, E ;
Daffara, R ;
Miserocchi, G ;
Palestini, P .
RESPIRATORY RESEARCH, 2006, 7 (1)
[6]  
Boyd NL, 2007, EXP BIOL MED, V232, P833
[7]   A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J].
Burns, Jennifer M. ;
Summers, Bretton C. ;
Wang, Yu ;
Melikian, Anita ;
Berahovich, Rob ;
Miao, Zhenhua ;
Penfold, Mark E. T. ;
Sunshine, Mary Jean ;
Littman, Dan R. ;
Kuo, Calvin J. ;
Wei, Kevin ;
McMaster, Brian E. ;
Wright, Kim ;
Howard, Maureen C. ;
Schall, Thomas J. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (09) :2201-2213
[8]   Enhanced expression of inducible nitric oxide synthase without vasodilator effect in chronically infected lungs [J].
Cadogan, E ;
Hopkins, N ;
Giles, S ;
Bannigan, JG ;
Moynihan, J ;
McLoughlin, P .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1999, 277 (03) :L616-L627
[9]   Bone morphogenetic proteins, their antagonists, and the skeleton [J].
Canalis, E ;
Economides, AN ;
Gazzerro, E .
ENDOCRINE REVIEWS, 2003, 24 (02) :218-235
[10]  
Cardoso WV, 2000, DEV DYNAM, V219, P121, DOI 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1053>3.3.CO