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Tytuł:
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miR-19a-3p downregulates tissue factor and functions as a potential therapeutic target for sepsis-induced disseminated intravascular coagulation.
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Autorzy:
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Zhang R; 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.
Lu S; Precision Medicine Key Laboratory of Sichuan Province and Precision Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Yang X; 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.
Li M; 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.
Jia H; 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.
Liao J; 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.
Jing Q; 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.
Wu Y; 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.
Wang H; 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.
Xiao F; 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.
Bai X; 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.
Na X; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
Kang Y; Institute of Environmental Information, Chinese Research Academy of Environmental Sciences, Beijing 100012, China. Electronic address: .
Wan L; 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: .
Yang J; 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: .
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Źródło:
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Biochemical pharmacology [Biochem Pharmacol] 2021 Oct; Vol. 192, pp. 114671. Date of Electronic Publication: 2021 Jul 09.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
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MeSH Terms:
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Disseminated Intravascular Coagulation/*metabolism
Down-Regulation/*physiology
Human Umbilical Vein Endothelial Cells/*metabolism
MicroRNAs/*biosynthesis
Sepsis/*metabolism
Thromboplastin/*metabolism
Animals ; Cells, Cultured ; Disseminated Intravascular Coagulation/chemically induced ; Down-Regulation/drug effects ; Female ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Infant, Newborn ; Lipopolysaccharides/toxicity ; Male ; Rats ; Rats, Sprague-Dawley ; Sepsis/chemically induced ; Thromboplastin/antagonists & inhibitors
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Contributed Indexing:
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Keywords: Biomarker; Coagulation cascade; Disseminated intravascular coagulation; Therapeutic target; Tissue factor; miR-19a-3p
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Substance Nomenclature:
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0 (Lipopolysaccharides)
0 (MIRN19 microRNA, human)
0 (MicroRNAs)
9035-58-9 (Thromboplastin)
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Entry Date(s):
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Date Created: 20210711 Date Completed: 20211116 Latest Revision: 20211116
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Update Code:
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20240105
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DOI:
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10.1016/j.bcp.2021.114671
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PMID:
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34246626
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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-κB) P65, NFKB inhibitor alpha (IκB-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-IκB-a/IκB-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.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
