title: Inhibition of MicroRNA 195 Prevents Apoptosis and Multiple-Organ Injury in Mouse Models of Sepsis.
abstract: BACKGROUND
  MicroRNAs (miRs) are a class of short RNA molecules, which negatively regulate gene expression. The levels of circulating miR-15 family members are elevated in septic patients and may be associated with septic death. This study investigated whether inhibition of miR-195, a member of the miR-15 family, provided beneficial effects in sepsis.
  
  
  RESULTS
  Sepsis was induced by injection of feces into the peritoneum in mice. miR-195 was upregulated in the lung and liver of septic mice. Silencing of miR-195 increased the protein levels of BCL-2, Sirt1, and Pim-1; prevented apoptosis; reduced liver and lung injury; and improved the survival in septic mice. Silencing of miR-195 provided similar protection in lipopolysaccharide-induced endotoxemic mice. In endothelial cells, upregulation of miR-195 induced apoptosis, and inhibition of miR-195 prevented lipopolysaccharide-induced apoptosis. miR-195 repressed expression of its protein targets, BCL-2, Sirt1, and Pim-1. Furthermore, overexpression of Pim-1 prevented apoptosis induced by lipopolysaccharide and miR-195 mimic. Inhibition of Pim-1 attenuated the protective effects of miR-195 silencing in septic mice.
  
  
  CONCLUSIONS
  Silencing of miR-195 reduced multiple-organ injury and improved the survival in sepsis, and the protective effects of miR-195 inhibition were associated with upregulation of Bcl-2, Sirt1, and Pim-1. Thus, inhibition of miR-195 may represent a new therapeutic approach for sepsis.
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes for Biology and Medical Sciences, Soochow University, Suzhou Lawson Health Research Institute Department of Medicine Department of Pathology, University of Western Ontario, London, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Western Ontario, London, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China.
authors.forename: Ruizhen
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.affiliation: Lawson Health Research Institute Department of Medicine.
authors.forename: Claudio
authors.initials: C
authors.lastname: Martin
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes for Biology and Medical Sciences, Soochow University, Suzhou.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes for Biology and Medical Sciences, Soochow University, Suzhou Lawson Health Research Institute Department of Medicine Department of Pathology, University of Western Ontario, London, Canada.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000628:therapy*; D005243:Feces; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009102:Multiple Organ Failure / Q000517:prevention & control*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D034622:RNA Interference; D018805:Sepsis / Q000139:chemically induced / Q000628:therapy*; D056564:Sirtuin 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; C569389:MIRN195a microRNA, mouse; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: apoptosis; miR-195; multiple-organ injury; sepsis