Yin Jie, Xia Weiwei, Zhang Yue, Ding Guixia, Chen Lihong, Yang Guangrui, Huang Songming, Jia Zhanjun, Zhang Aihua
Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China.
Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Heart Vessels. 2018 Nov;33(11):1411-1422. doi: 10.1007/s00380-018-1190-9. Epub 2018 May 23.
Endothelial cells (ECs) are crucial in maintaining vascular homeostasis. Endothelial dysfunction was involved in many cardiovascular diseases (CVDs). Recently, antimalarial medicine artemisinin and its derivatives including dihydroartemisinin (DHA) were found to be beneficial in some diseases including CVDs. Prostaglandin (PG) E is a known inflammatory mediator and plays important roles in cardiovascular system. This study was to investigate the role of DHA in regulating cyclooxygenase (COX)/PGE synthase (PGES)/PGE cascade and inflammation in ECs. After DHA treatment, the mRNA and protein levels of COX-2 were strikingly upregulated in time- and dose-dependent manners. In contrast, COX-1 was significantly downregulated. As expected, inhibition of COX-1 or COX-2 further reduced PGE production after DHA treatment. Moreover, DHA enhanced microsomal PGE synthase (mPGES)-2 and moderately modulated cytosolic PGE synthase (cPGES) with no effect on mPGES-1 expression. Importantly, DHA significantly reduced PGE levels in line with the upregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH, a key enzyme for prostaglandin degradation). Lastly, we observed that DHA not only reduced the PGE levels in tumor necrosis factor-α (TNF-α)-treated ECs but also blunted the upregulation of inflammatory cytokines of interleukin (IL)-6 and IL-1β induced by TNF-α or PGE. These findings demonstrated an important role of DHA in regulating PGE synthesis cascade and inflammation in ECs, suggesting a potential of DHA for the treatment of inflammatory vascular diseases.
内皮细胞（ECs）在维持血管稳态中起着关键作用。内皮功能障碍与许多心血管疾病（CVDs）有关。最近，发现抗疟药物青蒿素及其衍生物包括双氢青蒿素（DHA）对包括CVDs在内的一些疾病有益。前列腺素（PG）E是一种已知的炎症介质，在心血管系统中发挥重要作用。本研究旨在探讨DHA在调节内皮细胞中环氧化酶（COX）/前列腺素E合酶（PGES）/前列腺素E级联反应和炎症中的作用。DHA处理后，COX-2的mRNA和蛋白水平以时间和剂量依赖性方式显著上调。相比之下，COX-1显著下调。正如预期的那样，抑制COX-1或COX-2进一步降低了DHA处理后的前列腺素E生成。此外，DHA增强了微粒体前列腺素E合酶（mPGES）-2，并适度调节了胞质前列腺素E合酶（cPGES），而对mPGES-1的表达没有影响。重要的是，DHA显著降低了前列腺素E水平，这与15-羟基前列腺素脱氢酶（15-PGDH，前列腺素降解的关键酶）的上调一致。最后，我们观察到DHA不仅降低了肿瘤坏死因子-α（TNF-α）处理的内皮细胞中的前列腺素E水平，还减弱了TNF-α或前列腺素E诱导的白细胞介素（IL）-6和IL-1β炎症细胞因子的上调。这些发现证明了DHA在调节内皮细胞中前列腺素E合成级联反应和炎症中的重要作用，表明DHA在治疗炎症性血管疾病方面具有潜力。
