Guan Ruijuan, Yao Hongwei, Li Ziying, Qian Jing, Yuan Liang, Cai Zhou, Ding Mingjing, Liu Wei, Xu Jingyi, Li Yuanyuan, Sun Dejun, Wang Jian, Lu Wenju
State Key Laboratory of Respiratory Diseases, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
Key Laboratory of National Health Commission for the Diagnosis & Treatment of COPD, The People's Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia, China.
Toxicol Sci. 2021 Sep 28;183(2):352-362. doi: 10.1093/toxsci/kfab087.
Emphysema is one of the most important phenotypes for chronic obstructive pulmonary disease (COPD). Apoptosis in alveolar epithelial cells (AECs) causes the emphysematous alterations in the smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to attenuate mitochondrial dysfunction, oxidative stress, and to modulate apoptosis. It has been shown that sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, protects against cigarette smoke (CS)-induced emphysema/COPD in mice. However, the mechanisms underlying these findings remain unclear. Here, we investigate whether and how STS attenuates AEC apoptosis via a SIRT1-dependent mechanism. We found that STS treatment decreased CS extract (CSE)-induced apoptosis in human alveolar epithelial A549 cells. STS reduced oxidative stress, improved mitochondrial function and mitochondrial membrane potential (ΔΨm), and restored mitochondrial dynamics-related protein expression. Moreover, STS promoted mitophagy, and increased oxidative phosphorylation protein levels (complexes I-IV) in CSE-stimulated A549 cells. The protective effects of STS were associated with SIRT1 upregulation, because SIRT1 inhibition by EX 527 significantly attenuated or abolished the ability of STS to reverse the CSE-induced mitochondrial damage, oxidative stress, and apoptosis in A549 cells. In conclusion, STS ameliorates CSE-induced AEC apoptosis by improving mitochondrial function and reducing oxidative stress via enhancing SIRT1 pathway. These findings provide novel mechanisms underlying the protection of STS against CS-induced COPD.
肺气肿是慢性阻塞性肺疾病（COPD）最重要的表型之一。肺泡上皮细胞（AECs）凋亡导致吸烟者和COPD患者出现肺气肿改变。沉默调节蛋白1（SIRT1）能够减轻线粒体功能障碍、氧化应激，并调节细胞凋亡。已表明丹参酮IIA磺酸钠（STS），一种丹参酮IIA的水溶性衍生物，可保护小鼠免受香烟烟雾（CS）诱导的肺气肿/COPD。然而，这些发现背后的机制仍不清楚。在此，我们研究STS是否以及如何通过依赖SIRT1的机制减轻AEC凋亡。我们发现STS处理可降低CS提取物（CSE）诱导的人肺泡上皮A549细胞凋亡。STS降低了氧化应激，改善了线粒体功能和线粒体膜电位（ΔΨm），并恢复了线粒体动力学相关蛋白的表达。此外，STS促进了线粒体自噬，并增加了CSE刺激的A549细胞中氧化磷酸化蛋白水平（复合体I-IV）。STS的保护作用与SIRT1上调有关，因为EX 527抑制SIRT1显著减弱或消除了STS逆转CSE诱导的A549细胞线粒体损伤、氧化应激和凋亡的能力。总之，STS通过增强SIRT1途径改善线粒体功能并降低氧化应激，从而减轻CSE诱导的AEC凋亡。这些发现为STS预防CS诱导的COPD提供了新的机制。
