Document Detail

Gremlin plays a key role in the pathogenesis of pulmonary hypertension.
MedLine Citation:
PMID:  22247494     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated.
METHODS AND RESULTS: Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization.
CONCLUSIONS: These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension.
Edwina Cahill; Christine M Costello; Simon C Rowan; Susan Harkin; Katherine Howell; Martin O Leonard; Mark Southwood; Eoin P Cummins; Susan F Fitzpatrick; Cormac T Taylor; Nicholas W Morrell; Finian Martin; Paul McLoughlin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-13
Journal Detail:
Title:  Circulation     Volume:  125     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-22     Completed Date:  2012-04-06     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  920-30     Citation Subset:  AIM; IM    
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MeSH Terms
Anoxia / complications
Bone Morphogenetic Proteins / physiology
Cells, Cultured
Endothelial Cells / metabolism
Hypertension, Pulmonary / etiology*
Intercellular Signaling Peptides and Proteins / analysis,  physiology*
Signal Transduction
Vascular Resistance
Grant Support
RG/08/002/24718//British Heart Foundation; //British Heart Foundation
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/Grem1 protein, mouse; 0/Intercellular Signaling Peptides and Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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