Physiol. Genomics Journal of Applied Physiology
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Physiol. Genomics (January 17, 2006). doi:10.1152/physiolgenomics.00251.2005
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Submitted on October 14, 2005
Accepted on January 16, 2006

Inhibition of LINE-1 Expression in the Heart Decreases Ischemic Damage by Activation of Akt/PKB Signaling

Eliana Lucchinetti1, Jianhua Feng1, Rafaela da Silva1, Genrich V Tolstonog2, Marcus C Schaub3, Gerald G Schumann4, and Michael Zaugg1*

1 University Hospital Zurich, Cardiovascular Anesthesia Research Laboratory, Institute of Anesthesiology, Zurich, Switzerland; University of Zurich, Center for Integrative Human Physiology, Zurich, Switzerland
2 University of Hamburg, Heinrich-Pette Institute for Experimental Virology and Immunology, Hamburg, Germany
3 University of Zurich, Institute of Pharmacology and Toxicology, Zurich, Switzerland
4 Paul-Ehrlich Institut, Division of Human Retroelements, Langen, Germany

* To whom correspondence should be addressed. E-mail: michael.zaugg{at}usz.ch.

Microarray analyses indicate that ischemic and pharmacological preconditioning suppress overexpression of the non-LTR retrotransposon LINE-1 (L1) after schemia/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 (ODN) 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 the 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/PKB{beta} 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 LY294002, 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, while 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 antiischemic therapeutic strategy.




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