Imperial College London
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DrChristopherRhodes

Faculty of Medicine, National Heart & Lung Institute

Reader in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hopper:2016:10.1161/CIRCULATIONAHA.115.020617,
author = {Hopper, RK and Moonen, JA and Diebold, I and Cao, A and Rhodes, CJ and Tojais, NF and Hennigs, JK and Gu, M and Wang, L and Rabinovitch, M},
doi = {10.1161/CIRCULATIONAHA.115.020617},
journal = {Circulation},
pages = {1783--1794},
title = {In pulmonary arterial hypertension, reduced BMPR2 promotes rndothelial-to-mesenchymal transition via HMGA1 and its target slug},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020617},
volume = {133},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background—We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)–like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH.Methods and Results—We documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell–specific loss of Bmpr2 showed similar gene and protein changes.Conclusions—Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
AU  - Hopper,RK
AU  - Moonen,JA
AU  - Diebold,I
AU  - Cao,A
AU  - Rhodes,CJ
AU  - Tojais,NF
AU  - Hennigs,JK
AU  - Gu,M
AU  - Wang,L
AU  - Rabinovitch,M
DO  - 10.1161/CIRCULATIONAHA.115.020617
EP  - 1794
PY  - 2016///
SN  - 0009-7322
SP  - 1783
TI  - In pulmonary arterial hypertension, reduced BMPR2 promotes rndothelial-to-mesenchymal transition via HMGA1 and its target slug
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020617
UR  - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.115.020617
UR  - http://hdl.handle.net/10044/1/31823
VL  - 133
ER  -
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