title: GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells.
abstract: BACKGROUND
  Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).
  
  
  METHODS
  GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.
  
  
  RESULTS
  GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.
  
  
  CONCLUSIONS
  GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.
authors.affiliation: Clinic for Pulmonary Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Nickel
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Clemens L
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Lavinia
authors.initials: L
authors.lastname: Maegel
authors.forename: Johanna
authors.initials: J
authors.lastname: Rische
authors.forename: Florian
authors.initials: F
authors.lastname: Laenger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Clemens
authors.initials: C
authors.lastname: Sauer
authors.forename: Mark
authors.initials: M
authors.lastname: Greer
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.forename: Heiko A
authors.initials: HA
authors.lastname: Golpon
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis; D016022:Case-Control Studies; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D065627:Familial Primary Pulmonary Hypertension; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply*; D042282:Microdissection; D018919:Neovascularization, Physiologic; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D011994:Recombinant Proteins