Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension

J Exp Med. 2014 Feb 10;211(2):263-80. doi: 10.1084/jem.20111741. Epub 2014 Jan 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / antagonists & inhibitors
  • Bone Morphogenetic Protein Receptors, Type II / deficiency*
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Case-Control Studies
  • Child
  • Endothelial Cells / metabolism
  • Eukaryotic Initiation Factor-2 / metabolism
  • Familial Primary Pulmonary Hypertension
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism
  • MAP Kinase Signaling System
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocytes, Smooth Muscle / metabolism
  • Protein Biosynthesis
  • Protein Phosphatase 1 / metabolism
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Young Adult

Substances

  • Eukaryotic Initiation Factor-2
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • BMPR2 protein, human
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II
  • PPP1R15A protein, human
  • Protein Phosphatase 1