Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension.
Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.
The Vera Moulton Wall Center for Pulmonary Vascular Disease, 2 Department of Pediatrics, 3 Department of Surgery, 4 Department of Microbiology and Immunology, 5 Department of Medicine, and 6 Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
Hirofumi
H
Sawada
Toshie
T
Saito
Nils P
NP
Nickel
Tero-Pekka
TP
Alastalo
Jason P
JP
Glotzbach
Roshelle
R
Chan
Leila
L
Haghighat
Gabriele
G
Fuchs
Michael
M
Januszyk
Aiqin
A
Cao
Ying-Ju
YJ
Lai
Vinicio de Jesus
Vde J
Perez
Yu-Mee
YM
Kim
Lingli
L
Wang
Pin-I
PI
Chen
Edda
E
Spiekerkoetter
Yoshihide
Y
Mitani
Geoffrey C
GC
Gurtner
Peter
P
Sarnow
Marlene
M
Rabinovitch
D000293:Adolescent; D000328:Adult; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D042783:Endothelial Cells / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D055815:Young Adult
D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1