In:
The Journal of Pathology, Wiley, Vol. 233, No. 1 ( 2014-05), p. 7-17
Abstract:
Vascular remodelling is a hallmark of pulmonary hypertension ( PH ) and is characterized by enhanced proliferation of pulmonary artery smooth muscle cells ( PASMCs ). Accumulating evidence indicates a crucial role of transcription factors in the vascular remodelling processes. Here, we characterize the involvement of meprin β , a novel activator protein‐1 ( AP ‐1) effector molecule, in PH . Fra‐2 transgenic ( TG ) mice exhibited increased right ventricular systolic pressure ( RVSP ), accompanied by vascular remodelling and activation of the pro‐proliferative and pro‐fibrotic AKT pathway. Microarray studies revealed the collagen‐processing metalloprotease meprin β as the most up‐regulated gene in Fra‐2 TG mice. Its expression, increased at all investigated time points, preceded the decreased expression of MMPs and increased TGF β , followed by collagen deposition. Correspondingly, remodelled pulmonary arteries from explanted idiopathic pulmonary arterial hypertension ( IPAH ) patients' lungs exhibited pronounced expression of meprin β . Fra‐2 and meprin β expression in human PASMCs was regulated by PDGF‐BB and TGF β in a complementary fashion. Importantly, PDGF‐BB ‐dependent proliferation was attenuated by silencing AP ‐1 expression or by meprin β inhibition. This study delineates a novel molecular mechanism underlying PASMCs proliferation and extracellular matrix ( ECM ) deposition by identifying meprin β as an important mediator in regulating vascular remodelling processes. Thus, meprin β may represent a new molecule that can be targeted in pulmonary hypertension. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Type of Medium:
Online Resource
ISSN:
0022-3417
,
1096-9896
DOI:
10.1002/path.2014.233.issue-1
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
1475280-3
