Magnesium lithospermate B prevents phenotypic transformation of pulmonary arteries in rats with hypoxic pulmonary hypertension through suppression of NADPH oxidase
Magnesium lithospermate B prevents phenotypic transformation of pulmonary arteries in rats with hypoxic pulmonary hypertension through suppression of NADPH oxidase
复制标题
紫草酸镁 B 通过抑制 NADPH 氧化酶来预防缺氧性肺动脉高压大鼠的肺动脉表型转化
DOI：
10.1016/j.ejphar.2019.01.020
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发表时间：
2019-03-15
影响因子：
5
通讯作者：
Peng, Jun
中科院分区：
文献类型：
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作者：
Li, Tao;Luo, Xiu-Ju;Peng, Jun
石精镁B （MLB）在多种疾病中具有抗氧化、抗增殖等多种生物活性。然而，MLB在肺动脉高压（PAH）中的作用尚不清楚。本研究旨在探讨MLB对缺氧诱导的肺动脉平滑肌细胞（PASMCs）表型转化的影响及其机制。SD大鼠（或PASMCs）暴露于10% O-2 3周（或3% O-2 48小时），同时进行MLB或NADPH氧化酶（NOX）抑制剂干预。首先观察MLB对PASMCs血流动力学、肺血管重构和表型转化的影响。然后，检测其对氮氧化物（NOX2和NOX4）、ERK和p-ERK蛋白水平的影响。结果显示，MLB可抑制PAH大鼠右心室收缩压升高和肺动脉壁厚/血管外径比值升高，减轻PASMCs的表型转化（a-平滑肌肌动蛋白降低，骨桥蛋白升高），并伴有NOX （NOX2和NOX4）蛋白水平下调，ROS和H2O2生成减少，ERK磷酸化抑制。NOX抑制剂（VAS2870）在缺氧处理的pasmc中取得了与MLB相似的结果。基于以上观察，我们认为MLB能够通过抑制NOX/ROS/ERK通路阻止缺氧PAH大鼠肺动脉表型转化，MLB可能具有治疗PAH的潜力。
Magnesium lithospermate B (MLB) shows multiple biological activities including anti-oxidation and anti-proliferation in various diseases. However, the function of MLB in pulmonary arterial hypertension (PAH) is still unknown. This study aims to investigate the effect of MLB on hypoxia-induced phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs) and the underlying mechanisms. SD rats (or PASMCs) were exposed to 10% O-2 for 3 weeks (or 3% O-2 for 48 h) along with MLB or NADPH oxidase (NOX) inhibitor intervention. The effects of MLB on hemodynamics, pulmonary vascular remodeling and phenotypic transformation of PASMCs were observed first. Then, its effects on the protein levels of NOX (NOX2 and NOX4), ERK and p-ERK were examined. The results showed that MLB prevented the elevation in right ventricular systolic pressure and the increase in ratio of wall thickness to vessel external diameter of pulmonary arteries in PAH rats, and attenuated phenotypic transformation of PASMCs (decrease in a-smooth muscle actin while increase in osteopontin), accompanied by downregulation of NOX (NOX2 and NOX4) protein levels, decrease of ROS and H2O2 production, and suppression of the phosphorylation of ERK. NOX inhibitor (VAS2870) achieved similar results to that of MLB did in the hypoxia-treated PASMCs. Based on the observations, we conclude that MLB is able to prevent phenotypic transformation of pulmonary arteries in hypoxic PAH rats through suppression of NOX/ROS/ERK pathway, and MLB might have the potentials in PAH therapy.