Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension

• Published in: European journal of pharmacology Vol. 887; p. 173438
• Main Authors: Braga, Cássia Lisboa, Felix, Nathane Santanna, Teixeira, Douglas Esteves, Vieira, Juliana Borges, Silva-Aguiar, Rodrigo Pacheco, Bose, Rebecca Madureira, Antunes, Mariana Alves, Rocha, Nazareth de Novaes, Caruso-Neves, Celso, Cruz, Fernanda Ferreira, Rocco, Patricia Rieken Macedo, Silva, Pedro Leme
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-11-2020
• Subjects: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Lung - blood supply; Lung - drug effects; Lung - pathology; Male; Monocrotaline - toxicity; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - pathology; Niclosamide; Niclosamide - pharmacology; Niclosamide - therapeutic use; Pulmonary arterial hypertension; Pulmonary Arterial Hypertension - chemically induced; Pulmonary Arterial Hypertension - pathology; Pulmonary Arterial Hypertension - prevention & control; Rats; Rats, Wistar; Signal transducer and activator of transcription; Vascular remodeling; Vascular Remodeling - drug effects; Vascular Remodeling - physiology; Vascular remodeling; Niclosamide; Signal transducer and activator of transcription; Pulmonary arterial hypertension
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173438

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.
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•STAT-3 has been associated with vascular remodeling in PAH.•Niclosamide is known to inhibit STAT3 phosphorylation and has low toxicity.•Niclosamide with sildenafil improved vascular remodeling and cardiac function.•A new role for a well-established drug may represent a promising therapy for PAH.