Polygonum cuspidatum Exosome-Like Nanovesicles Alleviate Hypoxic Pulmonary Hypertension by Stabilizing PON1 to...

Hypoxic pulmonary hypertension (HPH) is characterized by excessive proliferation of pulmonary vascular cells, ultimately resulting in right heart failure and death. Although resveratrol, an active component of Polygonum cuspidatum (PC), has shown efficacy against HPH, the mechanism of PC exosome-like nanovesicles (PCELNs) in HPH remains unclear. PC exosome-like nanovesicles (PCELNs) were characterized using transmission electron microscopy, dynamic light scattering, and immunofluorescence (IF). A mouse HPH model was established by chronic hypoxic exposure. Hemodynamic parameters were measured, and pulmonary vascular pathology was assessed via H&E and Masson staining. Protein expression of PCNA, α-SMA, and OPN was analyzed by immunohistochemistry (IHC) and IF. Mouse primary PASMCs were isolated and cultured. Cell proliferation, apoptosis, and migration were evaluated using EdU assay, flow cytometry, and Transwell assay, respectively. Proteins related to phenotypic switching, autophagy, and the MAPK pathway were detected via Western blot. JC-1 staining, Mito-Tracker staining, IF, ATP/SOD assay kits, and flow cytometry were used to assess mitochondrial membrane potential, morphology, mitophagy, energy metabolism, and reactive oxygen species levels, respectively. Network pharmacology screened common targets of resveratrol and pulmonary hypertension, with molecular docking validating binding affinity. PC exosome-like nanovesicles (PCELNs) alleviated HPH, significantly improving pulmonary artery remodeling and hemodynamic indices in mice, inhibiting abnormal PASMC proliferation and migration, promoting apoptosis, and ameliorating mitochondrial function. The mechanism involves stabilizing paraoxonase 1 (PON1) expression, thereby suppressing MAPK pathway activation. PC exosome-like nanovesicles (PCELNs) alleviate HPH by enhancing PASMC phenotypic switching and mitigating mitochondrial dysfunction through the PON1/MAPK axis, providing a novel therapeutic strategy.