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1Research and 2Anesthesiology Services, Veterans Affairs Medical Center, and 3Department of Anesthesiology, Oregon Health and Sciences University, Portland, Oregon
Submitted 15 March 2004 ; accepted in final form 21 November 2004
Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K+ (KATP) channels. However, other elements of the Met5-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca2+-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 µM) did not. Treatment with herbimycin (1 µM) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr992 and Tyr1068. Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 µM) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 µM), and chelerythrine (2 µM). The PI3K inhibitor LY-294002 (20 µM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser473 was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.
peptides; opioid; opioid receptor; ischemic preconditioning; signaling
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