title: miR-34a-5p Inhibition Alleviates Intestinal Ischemia/Reperfusion-Induced Reactive Oxygen Species Accumulation and Apoptosis via Activation of SIRT1 Signaling.
abstract: Reactive oxygen species (ROS) generation and massive epithelial apoptosis are critical in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. We previously found that the Sirtuin 1 (SIRT1)-mediated antioxidant pathway was impaired in the intestine after I/R. Here, we investigate the potential role of SIRT1-targeting microRNAs (miRNAs) in regulating ROS accumulation and apoptosis in intestinal I/R, and the important role SIRT1 involved in.
  
  
  
  C57BL/6 mice were subjected to intestinal I/R induced by occlusion of the superior mesenteric artery followed by reperfusion. Caco-2 cells were incubated under hypoxia/reoxygenation condition to mimic I/R in vivo. We find that SIRT1 is gradually repressed during the early reperfusion, and that this repression results in intestinal ROS accumulation and apoptosis. Using bioinformatics analysis and real-time PCR, we demonstrate that miR-34a-5p and miR-495-3p are significantly increased among the 41 putative miRNAs that can target SIRT1. Inhibition of miR-34a-5p, but not miR-495-3p, attenuates intestinal I/R injury, as demonstrated by repressing p66shc upregulation, manganese superoxide dismutase repression, and the caspase-3 activation in vitro and in vivo; it further alleviates systemic injury, as demonstrated by reducing inflammatory cytokine release, attenuating lung and liver lesions, and improving survival. Interestingly, SIRT1 plays an indispensable role in the protection afforded by miR-34a-5p inhibition.
  
  
  
  This study provides the first evidence of miRNAs in regulating oxidative stress and apoptosis in intestinal I/R.
  
  
  
  miR-34a-5p knockdown attenuates intestinal I/R injury through promoting SIRT1-mediated suppression of epithelial ROS accumulation and apoptosis. This may represent a novel prophylactic approach to intestinal I/R injury. Antioxid. Redox Signal. 24, 961-973.
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Wang
authors.affiliation: 2 Department of Pharmacology, Dalian Medical University , Dalian, China .
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Guo
authors.initials: G
authors.lastname: Zu
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Feng
authors.affiliation: 2 Department of Pharmacology, Dalian Medical University , Dalian, China .
authors.forename: Wen
authors.initials: W
authors.lastname: Shan
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: 2 Department of Pharmacology, Dalian Medical University , Dalian, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 1 Department of General Surgery, The Second Hospital of Dalian Medical University , Dalian, China .
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tian
mesh_terms: D000818:Animals; D017209:Apoptosis; D018938:Caco-2 Cells; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply / Q000473:pathology; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1