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Background  Opioidergic SLP ( s ustained  l igand-activated  p reconditioning) 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.    Methodology/Principal Findings  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.

Unique Transcriptional Profile of Sustained Ligand-Activated Preconditioning in Pre- and Post-Ischemic Myocardium