Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α
| Autor: | Belinda L. Sun, Sara M. Camp, Heather Lynn, Ankit A. Desai, Xiaoguang Sun, Haiyang Tang, Rebecca Vanderpool, Franz Rischard, Jason X.-J. Yuan, Aleksandra Babicheva, Nancy Casanova, Liliana Moreno-Vinasco, Jian Wang, Geetanjali Gupta, Carrie L. Kempf, Mohamed Ahmed, Joe G.N. Garcia, Saad Sammani, Radu C. Oita, Akash Gupta |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pulmonary and Respiratory Medicine Transcription Genetic Hypertension Pulmonary medicine.medical_treatment Clinical Biochemistry Nicotinamide phosphoribosyltransferase Vascular Remodeling 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Basic Helix-Loop-Helix Transcription Factors medicine Transcriptional regulation Animals Humans Nicotinamide Phosphoribosyltransferase Molecular Biology Transcription factor Cells Cultured SOX Transcription Factors STAT5 Original Research biology Growth factor Endothelial Cells Cell Biology Rats Vascular endothelial growth factor Disease Models Animal 030104 developmental biology Gene Expression Regulation 030228 respiratory system chemistry Cancer research biology.protein STAT protein Cytokines Female Platelet-derived growth factor receptor |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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-β1 [transforming growth factor-β1], 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-2α (hypoxia-inducible factor-2α) also potently regulated NAMPT promoter activity, and HIF-2α 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-2α–dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling. |
| Databáze: | OpenAIRE |
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