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Meprin β , a novel mediator of vascular remodelling underlying pulmonary hypertension
Author(s) -
Biasin Valentina,
Marsh Leigh M,
Egemnazarov Bakytbek,
Wilhelm Jochen,
Ghanim Bahil,
Klepetko Walter,
Wygrecka Malgorzata,
Olschewski Horst,
Eferl Robert,
Olschewski Andrea,
Kwapiszewska Grazyna
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4303
Subject(s) - vascular remodelling in the embryo , matrix metalloproteinase , extracellular matrix , pulmonary hypertension , microbiology and biotechnology , pulmonary artery , metalloproteinase , gene silencing , biology , chemistry , cancer research , medicine , endocrinology , gene , biochemistry
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.