-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway

Autophagy has been greatly implicated in injured endothelial cells during pulmonary arterial hypertension (PAH). beta-arrestin1, a multifunctional cytoplasmic protein, has attracted considerable attention as an essential protective factor in PAH. However, its role in autophagy of injured pulmonary arterial endothelial cells (PAECs) remains to be determined. Here, we investigated the potential effects of beta-arrestin1 on autophagy and apoptosis in human PAECs (hPAECs) under hypoxic stress. Hypoxic stimuli increases autophagy and decreases the level of beta-arrestin1 in hPAECs. Furthermore, pathologic changes, namely increased proliferation, migration, and apoptosis resistance, are observed after hypoxia exposure. These are reversed after beta-arrestin1 overexpression (beta-arrestin1-OV) or treatment with 3-MA, an autophagy inhibitor. Finally, beta-arrestin1 suppresses the increase in autophagy and apoptosis resistance of hypoxic hPAECs. Mechanistically, beta-arrestin1 upregulates the activity of the Akt/mTOR signaling pathway and downregulates the expression of BNIP3 and Nix after hypoxic stress. Collectively, we have demonstrated, for the first time, that beta-arrestin1 reduces excessive autophagy and apoptosis resistance by activating the Akt/mTOR axis in hypoxic hPAECs. This knowledge suggests a promising therapeutic target for PAH.