PMID- 31820187 OWN - NLM STAT- MEDLINE DCOM- 20201119 LR - 20201119 IS - 1573-675X (Electronic) IS - 1360-8185 (Linking) VI - 25 IP - 1-2 DP - 2020 Feb TI - MicroRNA-214 targets COX-2 to antagonize indoxyl sulfate (IS)-induced endothelial cell apoptosis. PG - 92-104 LID - 10.1007/s10495-019-01582-4 [doi] AB - Cardiovascular disease (CVD) serves as the major cause of mortality in chronic kidney disease (CKD) patients. The injury of endothelium associated with the long-term challenge of uremic toxins including the toxic indoxyl sulfate (IS) is one of key pathological factors leading to CVD. However, the mechanisms of uremic toxins, especially the IS, resulting in endothelial injury, remain unclear. miR-214 was reported to contribute to the pathogenesis of cardiovascular diseases, while its role in IS-induced endothelial cell apoptosis is unknown. In this study, we investigated the role of microRNA-214 (miR-214) in IS-induced endothelial cell apoptosis and the underlying mechanisms using mouse aortic endothelial cells (MAECs). Following IS treatment, miR-214 was significantly downregulated in MAECs in line with enhanced cell apoptosis. Meanwhile, COX-2 was upregulated at both mRNA and protein levels along with increased secretion of PGE(2) in medium. To define the role of miR-214 in IS-induced endothelial cell apoptosis, we modulated miR-214 level in MAECs and found that overexpression of miR-214 markedly attenuated endothelial cell apoptosis, while antagonism of miR-214 deteriorated cell death after IS challenge. Further analyses confirmed that COX-2 is a target gene of miR-214, and the inhibition of COX-2 by a specific COX-2 inhibitor NS-398 strikingly attenuated IS-induced endothelial cell apoptosis along with a significant blockade of PGE(2) secretion. In conclusion, this study demonstrated an important role of miR-214 in protecting against endothelial cell damage induced by IS possibly by direct downregulation of COX-2/PGE(2) axis. FAU - Li, Shuzhen AU - Li S AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Xie, Yifan AU - Xie Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Yang, Bingyu AU - Yang B AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Huang, Songming AU - Huang S AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Zhang, Yue AU - Zhang Y AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. FAU - Jia, Zhanjun AU - Jia Z AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. jiazhanjun72@njmu.edu.cn. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. jiazhanjun72@njmu.edu.cn. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. jiazhanjun72@njmu.edu.cn. FAU - Ding, Guixia AU - Ding G AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. bhgyuan@163.com. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. bhgyuan@163.com. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. bhgyuan@163.com. FAU - Zhang, Aihua AU - Zhang A AD - Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People's Republic of China. zhaihua@njmu.edu.cn. AD - Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. zhaihua@njmu.edu.cn. AD - Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. zhaihua@njmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Netherlands TA - Apoptosis JT - Apoptosis : an international journal on programmed cell death JID - 9712129 RN - 0 (MicroRNAs) RN - 0 (Mirn214 microRNA, mouse) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - N187WK1Y1J (Indican) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Cyclooxygenase 2/genetics/*metabolism MH - Endothelial Cells/*cytology/drug effects/*metabolism MH - Humans MH - Indican/*toxicity MH - Male MH - Mice MH - MicroRNAs/genetics/*metabolism OTO - NOTNLM OT - Apoptosis OT - COX-2 OT - Endothelial cells OT - IS OT - MiR-214 EDAT- 2019/12/11 06:00 MHDA- 2020/11/20 06:00 CRDT- 2019/12/11 06:00 PHST- 2019/12/11 06:00 [pubmed] PHST- 2020/11/20 06:00 [medline] PHST- 2019/12/11 06:00 [entrez] AID - 10.1007/s10495-019-01582-4 [pii] AID - 10.1007/s10495-019-01582-4 [doi] PST - ppublish SO - Apoptosis. 2020 Feb;25(1-2):92-104. doi: 10.1007/s10495-019-01582-4.