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  • Title: Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension.
    Author: Braga CL, Felix NS, Teixeira DE, Vieira JB, Silva-Aguiar RP, Bose RM, Antunes MA, Rocha NN, Caruso-Neves C, Cruz FF, Rocco PRM, Silva PL.
    Journal: Eur J Pharmacol; 2020 Nov 15; 887():173438. PubMed ID: 32795515.
    Abstract:
    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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