Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling.

Détails

ID Serval
serval:BIB_11CD0E4F7666
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling.
Périodique
Physiological genomics
Auteur(s)
Lucchinetti E., Feng J., Silva Rd, Tolstonog G.V., Schaub M.C., Schumann G.G., Zaugg M.
ISSN
1531-2267 (Electronic)
ISSN-L
1094-8341
Statut éditorial
Publié
Date de publication
13/04/2006
Peer-reviewed
Oui
Volume
25
Numéro
2
Pages
314-324
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Microarray analyses indicate that ischemic and pharmacological preconditioning suppress overexpression of the non-long terminal repeat retrotransposon long interspersed nuclear element 1 (LINE-1, L1) after ischemia-reperfusion in the rat heart. We tested whether L1 overexpression is mechanistically involved in postischemic myocardial damage. Isolated, perfused rat hearts were treated with antisense or scrambled oligonucleotides (ODNs) against L1 for 60 min and exposed to 40 min of ischemia followed by 60 min of reperfusion. Functional recovery and infarct size were measured. Effective nuclear uptake was determined by FITC-labeled ODNs, and downregulation of L1 transcription was confirmed by RT-PCR. Immunoblot analysis was used to assess changes in expression levels of the L1-encoded proteins ORF1p and ORF2p. Immunohistochemistry was performed to localize ORF1/2 proteins in cardiac tissue. Effects of ODNs on prosurvival protein kinase B (Akt/PKB) expression and activity were also determined. Antisense ODNs against L1 prevented L1 burst after ischemia-reperfusion. Inhibition of L1 increased Akt/PKBbeta expression, enhanced phosphorylation of PKB at serine 473, and markedly improved postischemic functional recovery and decreased infarct size. Antisense ODN-mediated protection was abolished by LY-294002, confirming the involvement of the Akt/PKB survival pathway. ORF1p and ORF2p were found to be expressed in rat heart. ORF1p showed a predominantly nuclear localization in cardiomyocytes, whereas ORF2p was exclusively present in endothelial cells. ORF1p levels increased in response to ischemia, which was reversed by antisense ODN treatment. No significant changes in ORF2p were noted. Our results demonstrate that L1 suppression favorably affects postischemic outcome in the heart. Modifying transcriptional activity of L1 may represent a novel anti-ischemic therapeutic strategy.
Mots-clé
Animals, Chromones/pharmacology, Down-Regulation, Enzyme Inhibitors/pharmacology, Gene Expression Regulation, Heart/drug effects, In Vitro Techniques, Long Interspersed Nucleotide Elements/genetics, Male, Morpholines/pharmacology, Myocardial Infarction/enzymology, Myocardial Infarction/pathology, Myocardial Infarction/prevention & control, Myocardial Reperfusion Injury/enzymology, Myocardial Reperfusion Injury/pathology, Myocardial Reperfusion Injury/prevention & control, Myocardium/enzymology, Myocardium/pathology, Oligonucleotides, Antisense/genetics, Oligonucleotides, Antisense/metabolism, Open Reading Frames/genetics, Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Proteins/genetics, Proteins/metabolism, Proto-Oncogene Proteins c-akt/genetics, Proto-Oncogene Proteins c-akt/metabolism, RNA, Messenger/metabolism, Rats, Rats, Wistar, Signal Transduction
Pubmed
Web of science
Création de la notice
15/12/2017 17:16
Dernière modification de la notice
14/01/2020 7:26
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