PMID- 34246626 OWN - NLM STAT- MEDLINE DCOM- 20211116 LR - 20211116 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 192 DP - 2021 Oct TI - miR-19a-3p downregulates tissue factor and functions as a potential therapeutic target for sepsis-induced disseminated intravascular coagulation. PG - 114671 LID - S0006-2952(21)00284-7 [pii] LID - 10.1016/j.bcp.2021.114671 [doi] AB - Sepsis-induced disseminated intravascular coagulation (DIC) is a common life-threatening terminal-stage disease with high mortality. This study aimed to identify effective miRNAs as therapeutic targets for DIC. Bioinformatics and luciferase reporter gene analyses were performed to predict miR-19a-3p and validate that it targets tissue factor (TF). Quantitative real-time PCR was used to detect the expression of miR-19a-3p and TF, and TF procoagulant activity was determined using the chromogenic substrate method. Western blotting was used to detect the protein levels of TF, AKT serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK), nuclear factor kappa B (NF-kappaB) P65, NFKB inhibitor alpha (IkappaB-a) and their phosphorylated counterparts in cell experiments. Furthermore, a rat model was established to explore the potential of miR-19a-3p in DIC treatment. As a result, a human clinical study revealed that miR-19a-3p was downregulated and that TF was upregulated in neonates with sepsis-induced DIC compared with those in the control group. The luciferase reporter assay showed that TF was a direct target of miR-19a-3p. Cell experiments verified that the mRNA and protein levels of TF, and the p-AKT/AKT, p-Erk/Erk, p-P65/P65, p-IkappaB-a/IkappaB-a ratios, and TF procoagulant activity were significantly decreased in lipopolysaccharide (LPS) -induced human peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) inhibited by overexpression of miR-19a-3p, and that miR-19a-3p regulating TF was dependent on the NF-kB and AKT pathways. In vivo, miR-19a-3p injection into DIC rats suppressed the mRNA expression of TF; more importantly, significant improvements in coagulation function indicators and in histopathologies of lung and kidney were observed. In conclusion, miR-19a-3p may suppress DIC by targeting TF and might be a potential therapeutic target in treating sepsis-induced DIC. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Zhang, Rong AU - Zhang R AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Lu, Sifen AU - Lu S AD - Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China. FAU - Yang, Xudan AU - Yang X AD - Department of Pathology, Sichuan Academy of Medical Sciences＆Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Li, Maojun AU - Li M AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Jia, Hui AU - Jia H AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Liao, Jing AU - Liao J AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Jing, Qing AU - Jing Q AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Wu, Yanmei AU - Wu Y AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Wang, Haichuan AU - Wang H AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Xiao, Feng AU - Xiao F AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Bai, Xiaohong AU - Bai X AD - Department of Pediatrics, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. FAU - Na, Xiaoxue AU - Na X AD - School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China. FAU - Kang, Yulin AU - Kang Y AD - Institute of Environmental Information, Chinese Research Academy of Environmental Sciences, Beijing 100012, China. Electronic address: ylkang@pku.edu.cn. FAU - Wan, Ling AU - Wan L AD - Department of Ophthalmology, Sichuan Academy of Medical Sciences＆Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. Electronic address: wanling@med.uestc.edu.cn. FAU - Yang, Jiyun AU - Yang J AD - The Key Laboratory for Human Disease Gene Study of Sichuan Province, Prenatal Diagnosis Center, Sichuan Academy of Medical Sciences＆Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No.32, West section2, 1st ring road, Qingyang District, Chengdu, Sichuan 610072, China. Electronic address: yangjiyun@med.uestc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210709 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Lipopolysaccharides) RN - 0 (MIRN19 microRNA, human) RN - 0 (MicroRNAs) RN - 9035-58-9 (Thromboplastin) SB - IM MH - Animals MH - Cells, Cultured MH - Disseminated Intravascular Coagulation/chemically induced/*metabolism MH - Down-Regulation/drug effects/*physiology MH - Female MH - Human Umbilical Vein Endothelial Cells/drug effects/*metabolism MH - Humans MH - Infant, Newborn MH - Lipopolysaccharides/toxicity MH - Male MH - MicroRNAs/*biosynthesis MH - Rats MH - Rats, Sprague-Dawley MH - Sepsis/chemically induced/*metabolism MH - Thromboplastin/antagonists & inhibitors/*metabolism OTO - NOTNLM OT - Biomarker OT - Coagulation cascade OT - Disseminated intravascular coagulation OT - Therapeutic target OT - Tissue factor OT - miR-19a-3p EDAT- 2021/07/12 06:00 MHDA- 2021/11/17 06:00 CRDT- 2021/07/11 20:33 PHST- 2021/04/06 00:00 [received] PHST- 2021/06/30 00:00 [revised] PHST- 2021/07/01 00:00 [accepted] PHST- 2021/07/12 06:00 [pubmed] PHST- 2021/11/17 06:00 [medline] PHST- 2021/07/11 20:33 [entrez] AID - S0006-2952(21)00284-7 [pii] AID - 10.1016/j.bcp.2021.114671 [doi] PST - ppublish SO - Biochem Pharmacol. 2021 Oct;192:114671. doi: 10.1016/j.bcp.2021.114671. Epub 2021 Jul 9.