title: TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.
abstract: Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1-/-mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1-CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy.
  
  
  
  We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with (n = 23) and without (n = 16) PH. Compared with controls, lungs and distal PAs from PH patients showed induction of TSP1-CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA. In control PAs, treatment with exogenous TSP1 inhibited vasodilation and potentiated vasoconstriction to ET-1. Treatment of diseased PAs from PH patients with a CD47 blocking antibody improved sensitivity to vasodilators. Hypoxic wild type (WT) mice developed PH and displayed upregulation of pulmonary TSP1, CD47, and ET-1/ETA concurrent with down regulation of the transcription factor cell homolog of the v-myc oncogene (cMyc). In contrast, PH was attenuated in hypoxic CD47-/-mice while pulmonary TSP1 and ET-1/ETA were unchanged and cMyc was overexpressed. In CD47-/-pulmonary endothelial cells cMyc was increased and ET-1 decreased. In CD47+/+cells, forced induction of cMyc suppressed ET-1 transcript, whereas suppression of cMyc increased ET-1 signaling. Furthermore, disrupting TSP1-CD47 signaling in pulmonary smooth muscle cells abrogated ET-1-stimulated hypertrophy. Finally, a CD47 antibody given 2 weeks after monocrotaline challenge in rats upregulated pulmonary cMyc and improved aberrations in PH-associated cardiopulmonary parameters.
  
  
  
  In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1-CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.|Division of Renal and Electrolytes, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Starzl Transplant Institute, University of Pittsburgh, PA, USA.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Rogers
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sharifi-Sanjani
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ 85308, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Yao
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Kedar
authors.initials: K
authors.lastname: Ghimire
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Bienes-Martinez
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Mutchler
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Knupp
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baust
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Novelli
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Claudette
authors.initials: C
authors.lastname: St Croix
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Kutten
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Czajka
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Sembrat
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Hospital of the Princesa, Department of Medicine, Universidad Autónoma, Diego de León, 62 28006 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Labrousse-Arias
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Bachman
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.|Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.|Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Straub
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bilonick
authors.affiliation: Hospital of the Princesa, Department of Medicine, Universidad Autónoma, Diego de León, 62 28006 Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Calzada
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA jsi5@pitt.edu.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D062186:Arterial Pressure; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D014661:Vasoconstriction; D014664:Vasodilation; D055815:Young Adult
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; C497895:Cd47 protein, mouse; D019332:Endothelin-1; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019700:Thrombospondin 1; C000611726:thrombospondin-1, human; C585483:Thbs1 protein, mouse
keywords: CD47; Clinical pulmonary hypertension; ET-1; Thrombospondin-1; cMyc