BDNF/TrkB signaling augments smooth muscle cell proliferation in pulmonary hypertension.
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.
Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Giessen, Germany. Grazyna.Kwapiszewska@lvr.lbg.ac.at
Grazyna
G
Kwapiszewska
Karolina
K
Chwalek
Leigh M
LM
Marsh
Malgorzata
M
Wygrecka
Jochen
J
Wilhelm
Johannes
J
Best
Bakytbek
B
Egemnazarov
Friederike C
FC
Weisel
Sarah L
SL
Osswald
Ralph T
RT
Schermuly
Andrea
A
Olschewski
Werner
W
Seeger
Norbert
N
Weissmann
Oliver
O
Eickelberg
Ludger
L
Fink
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D007211:Indoles; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D011758:Pyrroles; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D051766:Early Growth Response Protein 1; D007211:Indoles; D008024:Ligands; D011758:Pyrroles; C116890:Semaxinib; D016686:Monocrotaline; D004247:DNA; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases