Fisetin alleviates pulmonary arterial hypertension by inhibiting the TGF-β1/Smad 2/3 signaling pathway
Abstract
Pulmonary arterial hypertension (PAH) is a refractory cardiopulmonary disorder with a high mortality rate and few treatment options. Fisetin, a natural flavonoid, exhibits pleiotropic effects including anti-angiogenic, anti-proliferative, anti-inflammatory, and autophagy-modulating activities. To evaluate the therapeutic potential of Fisetin, we established two experimental models: a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and a platelet-derived growth factor (PDGF)-induced human pulmonary artery smooth muscle cell (PASMC) proliferation model. The therapeutic efficacy and underlying mechanisms of Fisetin were comprehensively assessed using a combination of in vivo and in vitro approaches, including right heart catheterization, masson's trichrome and hematoxylin-eosin staining, immunohistochemistry, westernblot, immunofluorescence, ELISA, and transmission electron microscopy. Additionally, Protein-protein docking predicts interactions between proteins, whereas molecular docking predicts interactions between small molecules and proteins. Fisetin significantly ameliorated pulmonary vascular remodeling and reduced both right ventricular systolic pressure and the right ventricular hypertrophy index in monocrotaline (MCT)-induced PAH rats. The underlying mechanism may involve suppression of the TGF-β1/Smad2/3 pathway, which regulates autophagy, cell proliferation, migration, and inflammatory responses. In vitro, Fisetin exerted a…
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