Astragaloside IV alleviates hypoxic pulmonary hypertension by inhibiting RELM-β to reduce PINK1/Parkin-mediated mitophagy in pulmonary artery smooth muscle cells (PASMCs).

Abstract

Background and purpose: Hypoxic pulmonary hypertension (HPH) is a chronic disorder marked by irreversible pulmonary vascular remodelling (PVR) and pulmonary artery smooth muscle cell (PASMC) dysfunction. Astragaloside IV (AS-IV), a natural saponin from Astragalus, shows potential in HPH management. This study explores AS-IV's protective effect on PVR in HPH.

Experimental approach: HPH mouse model was established by 28 days of hypoxia and AS-IV was administered daily. The effect of AS-IV on the HPH model was evaluated by haemodynamic parameters, echocardiography and pathological changes in the pulmonary arteries. In vitro, CCK8, EdU, scratch and transwell assays assessed cell proliferation and migration. Transmission electron microscopy, immunofluorescence and Seahorse XFe24 were employed to detect mitochondrial morphology and function. Retnlb^-/- mice were constructed to assess the effect of RELM-β in HPH. The impact of AS-IV on RELM-β expression and mitophagy at the cellular level was evaluated through lentivirus overexpression.

Key results: AS-IV ameliorated HPH in mice by reducing right ventricular systolic pressure (RVSP), attenuating right ventricular hypertrophy and inhibiting vascular remodelling. AS-IV improves hypoxia-induced proliferation, migration and phenotypic transformation of PASMC in vitro. AS-IV reduced hypoxia-induced increases in RELM-β, PINK1, Parkin and excessive mitophagy. Retnlb (RELM-β) knockdown amended mitophagy and PVR under hypoxia. However, the overexpression of RETNLB (RELM-β) hindered the regulatory effect of AS-IV on mitophagy mediated by PINK1/Parkin pathways.

Conclusions and implications: AS-IV attenuated the hypoxia-induced increase of PASMC RELM-β expression and suppressed PINK1/Parkin-mediated mitophagy, resulting in the amelioration of PVR. This study unveils the potential of AS-IV as a therapeutic approach for HPH.