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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1604    most recent 00418.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Förster, K. Articles by Krieg, T. Search for Related Content PubMed PubMed Citation Articles by Förster, K. Articles by Krieg, T.

The -opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation

¹Department of Cardiology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany; and ²Department of Physiology, University of South Alabama, Mobile, Alabama

Submitted 4 April 2007 ; accepted in final form 29 May 2007

The specific -opioid receptor agonist [D-Ala²-D-Leu⁵]enkephalin (DADLE) protects against infarction in the heart when given before ischemia. In rabbit, this protection leads to phosphorylation of the pro-survival kinases Akt and extracellular signal-regulated kinase (ERK) and is dependent on transactivation of the epidermal growth factor receptor (EGFR). DADLE reportedly protects rat hearts at reperfusion. We therefore tested whether DADLE at reperfusion could protect isolated rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion and whether this protection is dependent on Akt, ERK, and EGFR. DADLE (40 nM) was infused for 1 h starting 5 min before reperfusion and reduced infarct size from 31.0 ± 2.3% in the control group to 14.6 ± 1.6% (P = 0.01). This protection was abolished by cotreatment of the metalloproteinase inhibitor (MPI) and the EGFR inhibitor AG1478. In contrast, 20 nM DADLE, although known to be protective before ischemia, failed to protect. Western blotting revealed that DADLE's protection was correlated to increase in phosphorylation of the kinases Akt and ERK1 and -2 in reperfused hearts (2.5 ± 0.5, 1.6 ± 0.2, and 2.3 ± 0.7-fold of baseline levels, P < 0.05 vs. control). The DADLE-dependent increases in Akt and ERK1/2 phosphorylation were abolished by either MPI or AG1478, confirming a signaling through the EGFR pathway. Additionally, DADLE treatment increased phosphorylation of EGFR (1.4 ± 0.2-fold, P = 0.03 vs. control). Thus the -opioid agonist DADLE protects rabbit hearts at reperfusion through activation of the pro-survival kinases Akt and ERK and is dependent on the transactivation of the EGFR.

akt cardioprotection; [D-Ala²-D-Leu⁵]enkephalin; epidermal growth factor receptor; extracellular signal-regulated kinase

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