PMID- 23058367 OWN - NLM STAT- MEDLINE DCOM- 20130501 LR - 20131121 IS - 1525-2191 (Electronic) IS - 0002-9440 (Linking) VI - 181 IP - 6 DP - 2012 Dec TI - BDNF/TrkB signaling augments smooth muscle cell proliferation in pulmonary hypertension. PG - 2018-29 LID - S0002-9440(12)00670-0 [pii] LID - 10.1016/j.ajpath.2012.08.028 [doi] AB - Pulmonary hypertension (PH) is a life-threatening disorder that is characterized by pulmonary arterial smooth muscle cell (PASMC) hyperplasia. Until now, little was been known about early changes that underlie the manifestation of PH. To characterize these early changes, we performed whole-genome microarray analysis of lungs from mice exposed to either 24 hours hypoxia or normoxia. TrkB, a member of the tyrosine kinase receptor family, and its ligand, brain-derived neurotrophic factor (BDNF), were strongly up-regulated in hypoxic mouse lungs, as well as in arteries of patients suffering from idiopathic pulmonary arterial hypertension (IPAH). BDNF stimulation of PASMC in vitro resulted in increased proliferation, TrkB and ERK1/2 phosphorylation, and nuclear translocation of the transcription factor early growth response factor 1 (Egr-1). In addition, increased Egr-1 expression was observed in idiopathic PAH lungs. The pro-proliferative effect of BDNF was attenuated by TrkB kinase inhibitor (K252a) or ERK1/2 inhibitor (U0126) pretreatment, and by knocking down Egr-1. Consequently, we have identified the BDNF-TrkB-ERK1/2 pathway as a proproliferative signaling pathway for PASMC in PH. Interference with this pathway may thus serve as an attractive reverse remodeling approach. CI - Copyright (c) 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Kwapiszewska, Grazyna AU - Kwapiszewska G AD - Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Giessen, Germany. Grazyna.Kwapiszewska@lvr.lbg.ac.at FAU - Chwalek, Karolina AU - Chwalek K FAU - Marsh, Leigh M AU - Marsh LM FAU - Wygrecka, Malgorzata AU - Wygrecka M FAU - Wilhelm, Jochen AU - Wilhelm J FAU - Best, Johannes AU - Best J FAU - Egemnazarov, Bakytbek AU - Egemnazarov B FAU - Weisel, Friederike C AU - Weisel FC FAU - Osswald, Sarah L AU - Osswald SL FAU - Schermuly, Ralph T AU - Schermuly RT FAU - Olschewski, Andrea AU - Olschewski A FAU - Seeger, Werner AU - Seeger W FAU - Weissmann, Norbert AU - Weissmann N FAU - Eickelberg, Oliver AU - Eickelberg O FAU - Fink, Ludger AU - Fink L LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121008 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Early Growth Response Protein 1) RN - 0 (Indoles) RN - 0 (Ligands) RN - 0 (Pyrroles) RN - 71IA9S35AJ (Semaxinib) RN - 73077K8HYV (Monocrotaline) RN - 9007-49-2 (DNA) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism/pharmacology MH - Cell Hypoxia/drug effects/genetics MH - Cell Proliferation/drug effects MH - DNA/metabolism MH - Disease Models, Animal MH - Early Growth Response Protein 1/metabolism MH - Enzyme Activation/drug effects MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Gene Expression Regulation/drug effects MH - Humans MH - Hypertension, Pulmonary/enzymology/*metabolism/*pathology MH - Indoles MH - Ligands MH - Lung/drug effects/metabolism/pathology MH - MAP Kinase Signaling System/drug effects/genetics MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Monocrotaline MH - Myocytes, Smooth Muscle/drug effects/enzymology/*metabolism/*pathology MH - Protein Binding/drug effects MH - Pyrroles MH - Rats MH - Receptor, trkB/genetics/*metabolism MH - *Signal Transduction/drug effects/genetics EDAT- 2012/10/13 06:00 MHDA- 2013/05/02 06:00 CRDT- 2012/10/13 06:00 PHST- 2012/03/12 00:00 [received] PHST- 2012/07/30 00:00 [revised] PHST- 2012/08/23 00:00 [accepted] PHST- 2012/10/13 06:00 [entrez] PHST- 2012/10/13 06:00 [pubmed] PHST- 2013/05/02 06:00 [medline] AID - S0002-9440(12)00670-0 [pii] AID - 10.1016/j.ajpath.2012.08.028 [doi] PST - ppublish SO - Am J Pathol. 2012 Dec;181(6):2018-29. doi: 10.1016/j.ajpath.2012.08.028. Epub 2012 Oct 8.