红景天苷通过 AhR/NF-κB 和 Nrf2/HO-1 通路保护肺动脉内皮细胞免受缺氧诱导的细胞凋亡。

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

机构信息

TAAHC-GDMU Biomedical and Health Joint R&D Center, The Provincial and Ministerial Co-founded Collaborative Innovation Center for R&D in Tibet Characteristic Agriculture and Animal Husbandry Resources, The Center for Xizang Chinese (Tibetan) Medicine Resource, Joint Laboratory for Tibetan Materia Medica Resource Scientific Protection and Utilization, Tibetan Medical Research Center of Tibet, Tibet Agriculture and Animal Husbandry University, Nyingchi, Tibet, PR China; Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, GDMU-TAAHC Biomedical and Health Joint R&D Center, Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, PR China.

Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, GDMU-TAAHC Biomedical and Health Joint R&D Center, Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, PR China; Laboratory of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, PR China.

出版信息

Phytomedicine. 2024 Jun;128:155376. doi: 10.1016/j.phymed.2024.155376. Epub 2024 Jan 18.

DOI:10.1016/j.phymed.2024.155376

PMID:38503152

Abstract

BACKGROUND

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.

PURPOSE

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.

STUDY DESIGN

Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O) 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% O for 48 h.

METHODS

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.

RESULTS

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.

CONCLUSIONS

SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.

摘要

背景

肺动脉内皮细胞（PAECs）的凋亡是导致肺动脉高压（PH）发展的一个重要因素，PH 是一种严重的心肺血管疾病。红景天苷（SAL）是一种源自红景天的生物活性化合物，但 SAL 对 PAECs 的潜在保护作用及其潜在机制仍不清楚。

目的

本研究旨在确定 SAL 在 PAECs 缺氧诱导凋亡中的作用，并探讨其潜在机制。

研究设计

雄性 Sprague-Dawley（SD）大鼠接受 10% O2 缺氧 4 周建立 PH 模型。大鼠每日腹腔注射 SAL（2、8 和 32mg/kg/d）或载体。为了明确 SAL 在 PAECs 中的分子机制，还通过将 PAECs 暴露于 1% O2 48 小时建立了缺氧细胞损伤的体外模型。

方法

采用苏木精-伊红（HE）染色、免疫荧光、流式细胞术、CCK-8、Western blot、qPCR、分子对接和表面等离子体共振（SPR）等技术，确定 SAL 在大鼠和体外 PAECs 中的作用。

结果

缺氧刺激增加 AhR 核易位并激活 NF-κB 信号通路，表现为 CYP1A1、CYP1B1、IL-1β 和 IL-6 的表达上调，导致氧化应激和炎症反应，最终导致 PAECs 凋亡。SAL 抑制 AhR 和 NF-κB 的激活，同时促进 Nrf2 的核易位，并增加其下游抗氧化蛋白 HO-1 和 NQO1 的表达，改善 PAECs 中的缺氧诱导的氧化应激。此外，SAL 降低了右心室收缩压，并降低了缺氧暴露大鼠的肺血管重构和右心室肥厚。