title: A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.
abstract: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific.
  
  
  
  To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart.
  
  
  
  MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1.
  
  
  
  A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury.
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States.
authors.forename: Shaurya
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address: n.bishopric@miami.edu.
authors.forename: Nanette H
authors.initials: NH
authors.lastname: Bishopric
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C488352:Lin-28 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C579635:Pik3ip1 protein, mouse; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Apoptosis; Ischemia-reperfusion; Lin28; PIK3IP1; let-7