Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways

• Published in: Phytomedicine (Stuttgart) 2024-06, Vol.128, p.155376-155376, Article 155376
• Main Authors: Lei, Wei, Chen, Mei-hong, Huang, Zu-feng, Chen, Xiao-ying, Wang, Jin-xia, Zheng, Jing, Zhu, Yi-zhun, Lan, Xiao-zhong, He, Yuan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Aryl hydrocarbon receptor; Endothelial Cells - drug effects; Glucosides - pharmacology; Heme Oxygenase (Decyclizing); Hypertension, Pulmonary - drug therapy; Hypoxia - drug therapy; Male; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Nuclear factor erythroid 2-related factor 2; Oxidative Stress - drug effects; Phenols - pharmacology; Pulmonary Artery - drug effects; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon - metabolism; Rhodiola - chemistry; Salidroside; Signal Transduction - drug effects
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2024.155376

•PAECs injury is the trigger for the development of pulmonary hypertension.•Molecular docking and surface plasmon resonance are used to confirm that the active compound salidroside from Rhodiola can effectively bind to the AhR.•For the first time, we demonstrated the mechanism by which salidroside affects PAECs via inhibition of AhR nuclear translocation.•Salidroside can protect PAECs from hypoxic injury through the AhR/NF-κB and Nrf2/HO-1 signaling pathways. The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1β, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.