Sacubitril/valsartan as a modulator of pulmonary fibrosis: insights into Lnc-SNHG-16/miR-455 modulation and Notch/Smad-3 pathway inhibition

Abstract

Pulmonary fibrosis is a progressive and life-threatening interstitial lung disease marked by excessive extracellular matrix accumulation and declining pulmonary function. Despite available therapies, clinical outcomes remain suboptimal, necessitating the exploration of novel therapeutic approaches. Sacubitril/valsartan, a dual-acting agent combining a neprilysin inhibitor and angiotensin II receptor blocker, has recently emerged as a candidate with potential anti-fibrotic properties. This study investigates the therapeutic efficacy of sacubitril/valsartan in a bleomycin-induced rat model of pulmonary fibrosis. The compound was administered orally once daily, beginning on the first day of fibrosis induction and continued for 21 days. Fibrotic progression was evaluated through biochemical and histological assessments, including quantification of hydroxyproline content, α-smooth muscle actin (α-SMA) expression, collagen deposition percentage, and histopathological examination of lung tissue. Molecular analyses revealed that sacubitril/valsartan significantly downregulated the expression of long non-coding RNA SNHG-16 and concurrently upregulated miR-455 levels. These changes were associated with suppression of the Notch-2/Smad-3 signaling pathway. Additionally, sacubitril/valsartan treatment resulted in a notable reduction in pulmonary levels of transforming growth factor-β (TGF-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), indicating attenuation of both fibrotic and inflammatory responses. Collectively, these findings suggest that sacubitril/valsartan mitigates pulmonary fibrosis through modulation of the SNHG-16/miR-455 axis and inhibition of the Notch-2/Smad-3/TGF-β signaling cascade, highlighting its potential as a promising therapeutic strategy for the management of pulmonary fibrosis.