title: MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury.
abstract: BACKGROUND
  MicroRNAs (miRs) participate in many cardiac pathophysiological processes, including ischemia/reperfusion (I/R)-induced cardiac injury. Recently, we and others observed that miR-494 was downregulated in murine I/R-injured and human infarcted hearts. However, the functional consequence of miR-494 in response to I/R remains unknown.
  
  
  RESULTS
  We generated a mouse model with cardiac-specific overexpression of miR-494. Transgenic hearts and wild-type hearts from multiple lines were subjected to global no-flow I/R with the Langendorff system. Transgenic hearts exhibited improved recovery of contractile performance over the reperfusion period. This improvement was accompanied by remarkable decreases in both lactate dehydrogenase release and the extent of apoptosis in transgenic hearts compared with wild-type hearts. In addition, myocardial infarction size was significantly reduced in transgenic hearts on I/R in vivo compared with wild-type hearts. Similarly, short-term overexpression of miR-494 in cultured adult cardiomyocytes demonstrated an inhibition of caspase-3 activity and reduced cell death on simulated I/R. In vivo treatment with antisense oligonucleotide miR-494 increased I/R-triggered cardiac injury relative to the administration of mutant antisense oligonucleotide miR-494 and saline controls. We further identified that 3 proapoptotic proteins (PTEN, ROCK1, and CaMKIIδ) and 2 antiapoptotic proteins (FGFR2 and LIF) were authentic targets for miR-494. Importantly, the Akt-mitochondrial signaling pathway was activated in miR-494-overexpressing myocytes.
  
  
  CONCLUSIONS
  Our findings suggest that although miR-494 targets both proapoptotic and antiapoptotic proteins, the ultimate consequence is activation of the Akt pathway, leading to cardioprotective effects against I/R-induced injury. Thus, miR-494 may constitute a new therapeutic agent for the treatment of ischemic heart disease.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Ren
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Liu
authors.forename: Junqi
authors.initials: J
authors.lastname: Yang
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Hu
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D051017:Apoptosis Regulatory Proteins; D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse