Autophagy has been greatly implicated in injured endothelial cells during pulmonary arterial hypertension (PAH). β-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 β-arrestin1 on autophagy and apoptosis in human PAECs (hPAECs) under hypoxic stress. Hypoxic stimuli increases autophagy and decreases the level of β-arrestin1 in hPAECs. Furthermore, pathologic changes, namely increased proliferation, migration, and apoptosis resistance, are observed after hypoxia exposure. These are reversed after β-arrestin1 overexpression (β-arrestin1-OV) or treatment with 3-MA, an autophagy inhibitor. Finally, β-arrestin1 suppresses the increase in autophagy and apoptosis resistance of hypoxic hPAECs. Mechanistically, β-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 β-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.

自噬在肺动脉高压（PAH）期间与受损的内皮细胞密切相关。β-arrestin1是一种多功能细胞质蛋白，作为PAH的重要保护因子已引起了广泛关注。但是，其在受损肺动脉内皮细胞（PAEC）自噬中的作用尚待确定。在这里，我们研究了低氧胁迫下β-arrestin1对人PAECs（hPAECs）自噬和细胞凋亡的潜在影响。缺氧刺激会增加hPAECs中的自噬并降低β-arrestin1的水平。此外，在低氧暴露后观察到病理变化，即增加的增殖，迁移和凋亡抗性。在β-arrestin1过表达（β-arrestin1-OV）或用3-MA（自噬抑制剂）治疗后，这些情况会逆转。最后，β-arrestin1抑制缺氧hPAECs自噬和细胞凋亡抗性的增加。从机制上讲，低氧应激后，β-arrestin1上调Akt / mTOR信号通路的活性，下调BNIP3和Nix的表达。总的来说，我们首次证明了β-arrestin1通过激活缺氧hPAECs中的Akt / mTOR轴来减少过度的自噬和细胞凋亡抗性。该知识表明PAH有希望的治疗靶标。β-arrestin1通过激活缺氧hPAECs中的Akt / mTOR轴来减少过度的自噬和细胞凋亡抗性。该知识表明PAH有希望的治疗靶标。β-arrestin1通过激活缺氧hPAECs中的Akt / mTOR轴来减少过度的自噬和细胞凋亡抗性。该知识表明PAH有希望的治疗靶标。