Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension

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 beta, 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 beta 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 beta, followed by collagen deposition. Correspondingly, remodelled pulmonary arteries from explanted idiopathic pulmonary arterial hypertension (IPAH) patients' lungs exhibited pronounced expression of meprin beta. Fra-2 and meprin beta expression in human PASMCs was regulated by PDGF-BB and TGF beta in a complementary fashion. Importantly, PDGF-BB-dependent proliferation was attenuated by silencing AP-1 expression or by meprin beta inhibition. This study delineates a novel molecular mechanism underlying PASMCs proliferation and extracellular matrix (ECM) deposition by identifying meprin beta as an important mediator in regulating vascular remodelling processes. Thus, meprin beta may represent a new molecule that can be targeted in pulmonary hypertension. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.