title: Unique transcriptional profile of sustained ligand-activated preconditioning in pre- and post-ischemic myocardium.
abstract: BACKGROUND
  Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3-5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium.
  
  
  RESULTS
  Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated genes in normoxic hearts from SLP mice (≥1.3-fold change, FDR≤5%). Induced genes encoded sarcomeric/contractile proteins (Myh7, Mybpc3,Myom2,Des), natriuretic peptides (Nppa,Nppb) and stress-signaling elements (Csda,Ptgds). Highly repressed genes primarily encoded chemokines (Ccl2,Ccl4,Ccl7,Ccl9,Ccl13,Ccl3l3,Cxcl3), cytokines (Il1b,Il6,Tnf) and other proteins involved in inflammation/immunity (C3,Cd74,Cd83, Cd86,Hla-dbq1,Hla-drb1,Saa1,Selp,Serpina3), together with endoplasmic stress proteins (known: Dnajb1,Herpud1,Socs3; putative: Il6, Gadd45g,Rcan1) and transcriptional controllers (Egr2,Egr3, Fos,Hmox1,Nfkbid). Biological themes modified thus related to inflammation/immunity, together with cellular/cardiovascular movement and development. SLP also modified the transcriptional response to I-R (46 genes uniquely altered post-ischemia), which may influence later infarction/remodeling. This included up-regulated determinants of cellular resistance to oxidant (Mgst3,Gstm1,Gstm2) and other forms of stress (Xirp1,Ankrd1,Clu), and repression of stress-response genes (Hspa1a,Hspd1,Hsp90aa,Hsph1,Serpinh1) and Txnip.
  
  
  CONCLUSIONS
  Protection via SLP is associated with transcriptional repression of inflammation/immunity, up-regulation of sarcomeric elements and natriuretic peptides, and modulation of cell stress, growth and development, while conventional protective molecules are unaltered.
authors.affiliation: Faculty of Health Sciences and Medicine, Bond University, Queensland, Australia. keashton@bond.edu.au
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Ashton
authors.forename: Amanda
authors.initials: A
authors.lastname: Tupicoff
authors.forename: Grant
authors.initials: G
authors.lastname: Williams-Pritchard
authors.forename: Can J
authors.initials: CJ
authors.lastname: Kiessling
authors.forename: Louise E
authors.initials: LE
authors.lastname: See Hoe
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: Jason N
authors.initials: JN
authors.lastname: Peart
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D019194:Ischemic Preconditioning; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017202:Myocardial Ischemia / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D008024:Ligands