PMID- 32142369
OWN - NLM
STAT- MEDLINE
DCOM- 20201013
LR  - 20230704
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 63
IP  - 1
DP  - 2020 Jul
TI  - Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular 
      Remodeling. Transcriptional Regulation by SOX and HIF-2alpha.
PG  - 92-103
LID - 10.1165/rcmb.2019-0164OC [doi]
AB  - We previously demonstrated involvement of NAMPT (nicotinamide 
      phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now 
      examine NAMPT regulation and extracellular NAMPT's (eNAMPT's) role in PAH 
      vascular remodeling. NAMPT transcription and protein expression in human lung 
      endothelial cells were assessed in response to PAH-relevant stimuli (PDGF 
      [platelet-derived growth factor], VEGF [vascular endothelial growth factor], 
      TGF-beta1 [transforming growth factor-beta1], and hypoxia). Endothelial-to-mesenchymal 
      transition was detected by SNAI1 (snail family transcriptional repressor 1) and 
      PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An 
      eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of 
      monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly 
      increased in patients with idiopathic pulmonary arterial hypertension, were 
      highly correlated with indices of PAH severity. eNAMPT increased 
      endothelial-to-mesenchymal transition, and each PAH stimulus significantly 
      increased endothelial cell NAMPT promoter activity involving transcription 
      factors STAT5 (signal transducer and activator of transcription 5), SOX18 
      (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a 
      PAH candidate gene newly defined by genome-wide association study. The 
      hypoxia-induced transcription factor HIF-2alpha (hypoxia-inducible factor-2alpha) also 
      potently regulated NAMPT promoter activity, and HIF-2alpha binding sites were 
      identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase 
      domain-containing protein 2) inhibitor FG-4592 significantly increased NAMPT 
      promoter activity and protein expression in an HIF-2alpha-dependent manner. Finally, 
      the eNAMPT-neutralizing polyclonal antibody significantly reduced 
      monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-kappaB 
      activation. eNAMPT is a novel and attractive therapeutic target essential to PAH 
      vascular remodeling.
FAU - Sun, Xiaoguang
AU  - Sun X
AUID- ORCID: 0000-0003-4226-8294
AD  - Department of Medicine.
FAU - Sun, Belinda L
AU  - Sun BL
AD  - Department of Pathology, and.
FAU - Babicheva, Aleksandra
AU  - Babicheva A
AD  - Department of Medicine.
FAU - Vanderpool, Rebecca
AU  - Vanderpool R
AD  - Department of Medicine.
FAU - Oita, Radu C
AU  - Oita RC
AUID- ORCID: 0000-0003-1378-8936
AD  - Department of Medicine.
FAU - Casanova, Nancy
AU  - Casanova N
AD  - Department of Medicine.
FAU - Tang, Haiyang
AU  - Tang H
AD  - Department of Medicine.
FAU - Gupta, Akash
AU  - Gupta A
AD  - Department of Medicine.
FAU - Lynn, Heather
AU  - Lynn H
AUID- ORCID: 0000-0001-8259-2326
AD  - Department of Medicine.
FAU - Gupta, Geetanjali
AU  - Gupta G
AD  - Department of Medicine.
FAU - Rischard, Franz
AU  - Rischard F
AD  - Department of Medicine.
FAU - Sammani, Saad
AU  - Sammani S
AD  - Department of Medicine.
FAU - Kempf, Carrie L
AU  - Kempf CL
AD  - Department of Medicine.
FAU - Moreno-Vinasco, Liliana
AU  - Moreno-Vinasco L
AD  - Department of Medicine.
FAU - Ahmed, Mohamed
AU  - Ahmed M
AD  - Department of Pediatrics, University of Arizona Health Sciences, Tucson, Arizona.
FAU - Camp, Sara M
AU  - Camp SM
AD  - Department of Medicine.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Medicine.
FAU - Desai, Ankit A
AU  - Desai AA
AD  - Department of Medicine.
FAU - Yuan, Jason X-J
AU  - Yuan JX
AD  - Department of Medicine.
FAU - Garcia, Joe G N
AU  - Garcia JGN
AUID- ORCID: 0000-0002-6934-0420
AD  - Department of Medicine.
LA  - eng
GR  - R01 HL141387/HL/NHLBI NIH HHS/United States
GR  - P30 CA023074/CA/NCI NIH HHS/United States
GR  - P01 HL134610/HL/NHLBI NIH HHS/United States
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - P50 HL073994/HL/NHLBI NIH HHS/United States
GR  - R01 HL136603/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Cytokines)
RN  - 0 (SOX Transcription Factors)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase)
RN  - EC 2.4.2.12 (nicotinamide phosphoribosyltransferase, human)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*genetics
MH  - Cells, Cultured
MH  - Cytokines/*genetics
MH  - Disease Models, Animal
MH  - Endothelial Cells/pathology
MH  - Female
MH  - Gene Expression Regulation/genetics
MH  - Humans
MH  - Hypertension, Pulmonary/*genetics
MH  - Male
MH  - Nicotinamide Phosphoribosyltransferase/*genetics
MH  - Rats
MH  - SOX Transcription Factors/*genetics
MH  - Transcription, Genetic/*genetics
MH  - Vascular Remodeling/*genetics
PMC - PMC7328254
OTO - NOTNLM
OT  - endothelial-to-mesenchymal transition
OT  - hypoxia-inducible factor-2alpha
OT  - nicotinamide phosphoribosyltransferase
OT  - promoter activity
OT  - pulmonary arterial hypertension
EDAT- 2020/03/07 06:00
MHDA- 2020/10/21 06:00
PMCR- 2021/07/01
CRDT- 2020/03/07 06:00
PHST- 2020/03/07 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2020/03/07 06:00 [entrez]
PHST- 2021/07/01 00:00 [pmc-release]
AID - 10.1165/rcmb.2019-0164OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2020 Jul;63(1):92-103. doi: 10.1165/rcmb.2019-0164OC.