TY - JOUR T1 - SMAD3 regulation contributes to lung vascular remodeling in pulmonary arterial hypertension JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2015.OA3496 VL - 46 IS - suppl 59 SP - OA3496 AU - Diana Zabini AU - Andras Kapus AU - Wolfgang Kuebler Y1 - 2015/09/01 UR - http://erj.ersjournals.com/content/46/suppl_59/OA3496.abstract N2 - Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by remodelling of pulmonary arteries, smooth muscle cell hyperplasia and hypertrophy. TGF-β, regulating cell proliferation, migration, and cell death, is elevated in PAH, and has been implicated in its pathogenesis based on clinical and experimental data. TGF-β binding to its receptor activates downstream signalling cascades, such as SMAD proteins. Recent data suggest that SMAD3 is downregulated in PAH. We thus hypothesize that loss of SMAD3 contributes to two major features of PAH: proliferation and hypertrophy (via disinhibition of the myocardin-related transcription factor (MRTF), a myogenic gene inducer). Here, we investigated the regulation of SMAD3 and its interaction with MRTF in human pulmonary arterial smooth muscle cells (PASMC) in vitro and in vivo, and its potential role in PAH.Results: TGF-β treatment for 72 h caused a significant downregulation of SMAD3 mRNA and protein levels in PASMC. Loss of SMAD3 was also evident in pulmonary arteries from rats with monocrotaline-induced PAH. Silencing of SMAD3 in PASMCs increased the proliferative response upon stimulation with fetal calf serum as determined by western blotting for proliferating cell nuclear antigen protein, Ki-67 positive cells, and bromodeoxyuridine assay. Co-immunoprecipitation revealed a reduced interaction between SMAD3 and MRTF in TGF-β treated PASMCs compared to control cells.Conclusion: The present data suggest that SMAD3 downregulation, which occurs in PASMC both in vitro and in vivo, contributes to increased proliferation and - through MRTF liberation - to hypertrophy of PASMC, key features of lung vascular remodeling in PAH. ER -