title: Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice.
abstract: Sepsis poses a serious global health problem with an overall mortality rate of 30%, in which the vascular injury is a major contributor. The study is to determine the expression profile of micro-RNAs in endotoxic vascular walls and their potential roles in sepsis-related vascular injury.
  
  
  
  Prospective randomized study.
  
  
  
  Laboratory investigation.
  
  
  
  Male C57BL/6 mice, average weight 26.5 ± 1.8 g.
  
  
  
  Endotoxemia was induced in mice via lipopolysaccharide injection (20 mg/kg, intraperitoneal) (Sigma, St. Louis, MO). The control mice were injected with the same amount of saline (500 μL, intraperitoneal). In a subgroup of mice, a high dose of lipopolysaccharide (30 mg/kg, intraperitoneal) was applied to induce endotoxin-related death.
  
  
  
  The mi-RNA expression profiles in aortas from lipopolysaccharide-induced endotoxic mice were determined. The result demonstrated that some micro-RNAs were aberrantly expressed in endotoxic mouse arteries. Among them, the endothelial cell-enriched/endothelial cell-specific miR-126a-3p was significantly down-regulated in endotoxic mouse arteries, septic human vessels, as well as vascular endothelial cells isolated from endotoxic mice or treated with lipopolysaccharide. The down-regulation of miR-126a-3p occurred at transcriptional level via the decreased expression of Krüppel-like factor 2, which could be inhibited by Krüppel-like factor 2 over-expression via adenovirus expressing Krüppel-like factor 2. The down-regulation of miR-126a-3p in endothelial cells resulted in the increased apoptosis, and decreased proliferation and migration, which were inhibited by miR-126a-3p mimics. In vivo, over-expression of miR-126a-3p via lentivirus attenuated endotoxemia-induced injuries on endothelial function and vascular permeability. We found that SPRED1 and VCAM-1 were two direct target genes of miR-126a-3p related to miR-126a-3p-mediated effects in endotoxemia. Finally, the survival rate of endotoxic mice was significantly increased by the over-expression of miR-126a-3p.
  
  
  
  The results suggest that vascular micro-RNAs such as miR-126a-3p may represent novel mechanisms and new therapeutic targets for endotoxemia-induced vascular injury and endotoxic mortality.
authors.affiliation: Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Maoping
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Qin
authors.affiliation: Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Rongzhou
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Han
authors.affiliation: Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Cardiovascular Research Center, Rush Medical College, Rush University Medical Center, Chicago, IL, USA, 60612.|Children's Heart Center, the Second Affiliated Hospital & Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, China, 325027.
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001011:Aorta / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000473:pathology*; D019446:Endotoxemia / Q000503:physiopathology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D011446:Prospective Studies; D011897:Random Allocation; D012097:Repressor Proteins / Q000235:genetics; D012867:Skin / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D035683:MicroRNAs; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; D019010:Vascular Cell Adhesion Molecule-1