Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension
Copyright © 2020 Elsevier B.V. All rights reserved..
Despite advances in medical therapy, pulmonary arterial hypertension (PAH) remains an inexorably progressive and highly lethal disease. Signal transducer and activator of transcription (STAT)-3 is one of the main intracellular transcription factors implicated in PAH vascular remodeling. We hypothesized that niclosamide, a STAT3 inhibitor, would reduce vascular remodeling in an established pulmonary arterial hypertension model, thus enhancing cardiac function. Male Wistar rats were treated either with monocrotaline (60 mg/kg), to induce PAH, or saline (C group) by intraperitoneal injection. On day 14, PAH animals were randomly assigned to receive oral (1) saline (PAH-SAL); (2) niclosamide (75 mg/kg/day) (PAH-NICLO); (3) sildenafil (20 mg/kg/day) (PAH-SIL); or (4) niclosamide + sildenafil (PAH-NICLO + SIL), once daily for 14 days. On day 28, right ventricular systolic pressure was lower in all treated groups compared to PAH-SAL. Pulmonary vascular collagen content was lower in PAH-NICLO (37 ± 3%) and PAH-NICLO + SIL (37 ± 6%) compared to PAH-SAL (68 ± 4%), but not in PAH-SIL (52 ± 1%). CD-34, an endothelial cell marker, was higher, while vimentin, a mesenchymal cell marker, was lower in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL, suggesting attenuation of endothelial-mesenchymal transition. Expression of STAT3 downstream targets such as transforming growth factor (TGF)-β, hypoxia-inducible factor (HIF)-1, and provirus integration site for Moloney murine leukemia virus (PIM-1) in lung tissue was reduced in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL. In conclusion, niclosamide, with or without sildenafil, mitigated vascular remodeling and improved right ventricle systolic pressure. This new role for a well-established drug may represent a promising therapy for PAH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:887 |
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| Enthalten in: |
European journal of pharmacology - 887(2020) vom: 15. Nov., Seite 173438 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Braga, Cássia Lisboa [VerfasserIn] |
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| Links: |
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| Themen: |
73077K8HYV |
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| Anmerkungen: |
Date Completed 17.05.2021 Date Revised 17.05.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejphar.2020.173438 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313701741 |
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| 245 | 1 | 0 | |a Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension |
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| 520 | |a Copyright © 2020 Elsevier B.V. All rights reserved. | ||
| 520 | |a Despite advances in medical therapy, pulmonary arterial hypertension (PAH) remains an inexorably progressive and highly lethal disease. Signal transducer and activator of transcription (STAT)-3 is one of the main intracellular transcription factors implicated in PAH vascular remodeling. We hypothesized that niclosamide, a STAT3 inhibitor, would reduce vascular remodeling in an established pulmonary arterial hypertension model, thus enhancing cardiac function. Male Wistar rats were treated either with monocrotaline (60 mg/kg), to induce PAH, or saline (C group) by intraperitoneal injection. On day 14, PAH animals were randomly assigned to receive oral (1) saline (PAH-SAL); (2) niclosamide (75 mg/kg/day) (PAH-NICLO); (3) sildenafil (20 mg/kg/day) (PAH-SIL); or (4) niclosamide + sildenafil (PAH-NICLO + SIL), once daily for 14 days. On day 28, right ventricular systolic pressure was lower in all treated groups compared to PAH-SAL. Pulmonary vascular collagen content was lower in PAH-NICLO (37 ± 3%) and PAH-NICLO + SIL (37 ± 6%) compared to PAH-SAL (68 ± 4%), but not in PAH-SIL (52 ± 1%). CD-34, an endothelial cell marker, was higher, while vimentin, a mesenchymal cell marker, was lower in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL, suggesting attenuation of endothelial-mesenchymal transition. Expression of STAT3 downstream targets such as transforming growth factor (TGF)-β, hypoxia-inducible factor (HIF)-1, and provirus integration site for Moloney murine leukemia virus (PIM-1) in lung tissue was reduced in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL. In conclusion, niclosamide, with or without sildenafil, mitigated vascular remodeling and improved right ventricle systolic pressure. This new role for a well-established drug may represent a promising therapy for PAH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Niclosamide | |
| 650 | 4 | |a Pulmonary arterial hypertension | |
| 650 | 4 | |a Signal transducer and activator of transcription | |
| 650 | 4 | |a Vascular remodeling | |
| 650 | 7 | |a Monocrotaline |2 NLM | |
| 650 | 7 | |a 73077K8HYV |2 NLM | |
| 650 | 7 | |a Niclosamide |2 NLM | |
| 650 | 7 | |a 8KK8CQ2K8G |2 NLM | |
| 700 | 1 | |a Felix, Nathane Santanna |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira, Douglas Esteves |e verfasserin |4 aut | |
| 700 | 1 | |a Vieira, Juliana Borges |e verfasserin |4 aut | |
| 700 | 1 | |a Silva-Aguiar, Rodrigo Pacheco |e verfasserin |4 aut | |
| 700 | 1 | |a Bose, Rebecca Madureira |e verfasserin |4 aut | |
| 700 | 1 | |a Antunes, Mariana Alves |e verfasserin |4 aut | |
| 700 | 1 | |a Rocha, Nazareth de Novaes |e verfasserin |4 aut | |
| 700 | 1 | |a Caruso-Neves, Celso |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Fernanda Ferreira |e verfasserin |4 aut | |
| 700 | 1 | |a Rocco, Patricia Rieken Macedo |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Pedro Leme |e verfasserin |4 aut | |
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