Chen Mayun, Cai Hui, Yu Chang, Wu Peiliang, Fu Yangyang, Xu Xiaomei, Fan Rong, Xu Cunlai, Chen Yanfan, Wang Liangxing, Huang Xiaoying
Division of Pulmonary Medicine, First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung Wenzhou, Zhejiang 325000, China.
Department of Radiology, First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang 325000, China.
Am J Transl Res. 2016 Jan 15;8(1):12-27. eCollection 2016.
Salidroside, an active ingredient isolated from Rhodiola rosea, has shown to exert protective effects against chronic hypoxia-induced pulmonary arterial hypertension (PAH). However, the underlying mechanisms were not well known. Based on our recent reports, we predicted the involvement of adenosine monophosphate-activated protein kinase (AMPK) mediated effects in salidroside regulation of PAH. Firstly, to prove the hypothesis, rats were exposed to chronic hypoxia and treated with increasing concentrations of salidroside or a selective AMPK activator-5'-aminoimidazole-4-carboxamide ribonucleoside (AICAR) for 4 weeks. After salidroside or AICAR treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary artery remodeling were attenuated. Then the effects of salidroside or AICAR on hypoxia-induced excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs), which contributed to pulmonary arterial remodeling, were investigated. Our results suggested salidroside, as well as AICAR, reversed hypoxia-induced PASMCs proliferation and apoptosis resistance while AMPK inhibitor Compound C enhanced the effects of hypoxia. To reveal the potential cellular mechanisms, activation of AMPKα1 and expression of the genes related to proliferation and apoptosis were analyzed in PASMCs after salidroside treatment under hypoxia conditions. The results demonstrated salidroside as well as AICAR might inhibit chronic hypoxia-induced PASMCs proliferation via AMPKα1-P53-P27/P21 pathway and reverse apoptosis resistance via AMPKα1-P53-Bax/Bcl-2-caspase 9-caspase 3 pathway.
红景天苷是从红景天中分离出的一种活性成分，已显示出对慢性缺氧诱导的肺动脉高压（PAH）具有保护作用。然而，其潜在机制尚不清楚。基于我们最近的报告，我们推测腺苷单磷酸激活的蛋白激酶（AMPK）介导的效应参与了红景天苷对PAH的调节。首先，为了验证这一假设，将大鼠暴露于慢性缺氧环境，并分别用浓度递增的红景天苷或选择性AMPK激活剂5'-氨基咪唑-4-甲酰胺核苷（AICAR）处理4周。红景天苷或AICAR处理后，慢性缺氧诱导的右心室肥大和肺动脉重塑得到缓解。然后研究了红景天苷或AICAR对缺氧诱导的肺动脉平滑肌细胞（PASMCs）过度细胞增殖和抗凋亡的影响，这些因素导致了肺动脉重塑。我们的结果表明，红景天苷以及AICAR可逆转缺氧诱导的PASMCs增殖和抗凋亡，而AMPK抑制剂化合物C则增强了缺氧的影响。为了揭示潜在的细胞机制，在缺氧条件下红景天苷处理后的PASMCs中分析了AMPKα1的激活以及与增殖和凋亡相关基因的表达。结果表明，红景天苷以及AICAR可能通过AMPKα1-P53-P27/P21途径抑制慢性缺氧诱导的PASMCs增殖，并通过AMPKα1-P53-Bax/Bcl-2-半胱天冬酶9-半胱天冬酶3途径逆转抗凋亡作用。
