title: Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension.
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 TGFβ, 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 TGFβ 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.
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Valentina
authors.initials: V
authors.lastname: Biasin
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.forename: Bakytbek
authors.initials: B
authors.lastname: Egemnazarov
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005355:Fibrosis; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; D020574:Proto-Oncogene Proteins c-sis; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000077214:Becaplermin; D003094:Collagen; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C053833:meprin A
keywords: extracellular matrix; protease; pulmonary hypertension