Role of dihydroartemisinin in regulating prostaglandin E2 synthesis cascade and inflammation in endothelial cells.
Role of dihydroartemisinin in regulating prostaglandin E2 synthesis cascade and inflammation in endothelial cells.
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双氢青蒿素在调节前列腺素 E2 合成级联和内皮细胞炎症中的作用。
DOI：
10.1007/s00380-018-1190-9
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发表时间：
2018
影响因子：
1.5
通讯作者：
Zhang Aihua
中科院分区：
文献类型：
--
作者：
Yin Jie;Xia Weiwei;Zhang Yue;Ding Guixia;Chen Lihong;Yang Guangrui;Huang Songming;Jia Zhanjun;Zhang Aihua
内皮细胞（EC）在维持血管稳态中起着至关重要的作用。内皮功能障碍与多种心血管疾病（CVD）有关。最近，抗疟药青蒿素及其衍生物，包括双氢青蒿素（DHA）被发现是有益的，在一些疾病，包括心血管疾病。前列腺素E2（Prostaglandin，PG）是一种已知的炎症介质，在心血管系统中起重要作用。本研究旨在探讨DHA对内皮细胞环氧化酶（考克斯）/前列腺素E合成酶（PGES）/前列腺素E 2（PGE 2）级联反应及炎症反应的调节作用。DHA处理后，考克斯-2的mRNA和蛋白水平显著上调，呈时间和剂量依赖性。相反，考克斯-1显著下调。正如预期的那样，抑制考克斯-1或考克斯-2进一步减少DHA治疗后PGE 2的产生。此外，DHA增强微粒体PGE 2合酶（mPGES）-2和适度调节细胞溶质PGE 2合酶（cPGES），而对mPGES-1表达无影响。重要的是，DHA显著降低了PGE 2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EC中的PGE 2水平，而且减弱了TNF-α或PGE 2诱导的炎症细胞因子白细胞介素（IL）-6和IL-1β的上调。这些发现表明DHA在调节内皮细胞PGE 2合成级联和炎症中具有重要作用，提示DHA在治疗炎症性血管疾病中具有潜力。
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) E2is 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)/PGE2cascade 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 PGE2production after DHA treatment. Moreover, DHA enhanced microsomal PGE2synthase (mPGES)-2 and moderately modulated cytosolic PGE2synthase (cPGES) with no effect on mPGES-1 expression. Importantly, DHA significantly reduced PGE2levels 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 PGE2levels 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 PGE2. These findings demonstrated an important role of DHA in regulating PGE2synthesis cascade and inflammation in ECs, suggesting a potential of DHA for the treatment of inflammatory vascular diseases.