| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA
2 Research Service, Veterans Affairs Medical Center, Portland, OR, USA; Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA; Department of Anesthesiology, Oregon Health & Sciences University, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: donna.vanwinkle{at}med.va.gov.
Objective. Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial KATP channels. However, other elements of the Met5-enkephalin (ME) cardioprotection signaling pathway are not fully characterized. In the present study we investigated the role of tyrosine kinase, MAPK, and PI3K signaling pathways in ME-induced protection. Methods. Calcium-tolerant adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia (SI) for 180 min. ME was administered 15 min before the 180 min SI; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time.Results. The EGFR kinase inhibitor AG1478 (250 nM) blocked ME-induced protection, but the inactive analog AG9 (100 µM) did not. In addition, 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 MAP kinase inhibitor PD98059 (10 nM), and the specific MEK1/2 inhibitor U0126 (10 µM), also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD98059, the EGFR kinase inhibitor PD153035 (10 µM), and chelerythrine (2 µM). The PI3-kinase inhibitor LY294002 (20 µM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser473 was suppressed by LY294002, PD153035, and chelerythrine. Conclusion. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation the PI3K and MAPK pathways.
This article has been cited by other articles:
|
|
 |
|
  M. J. Merkel, L. Liu, Z. Cao, W. Packwood, P. D. Hurn, and D. M. Van Winkle Estradiol abolishes reduction in cell death by the opioid agonist Met5-enkephalin after oxygen glucose deprivation in isolated cardiomyocytes from both sexes Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H409 - H415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S De Minicis, C Candelaresi, M Marzioni, S Saccomano, T Roskams, A Casini, A Risaliti, R Salzano, N Cautero, F di Francesco, et al. Role of endogenous opioids in modulating HSC activity in vitro and liver fibrosis in vivo Gut, March 1, 2008; 57(3): 352 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Cao, L. Liu, W. Packwood, M. Merkel, P. D. Hurn, and D. M. Van Winkle Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection: role of PI3K/Akt Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H302 - H310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Forster, A. Kuno, N. Solenkova, S. B. Felix, and T. Krieg The {delta}-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1604 - H1608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Demyanets, C. Kaun, K. Rychli, G. Rega, S. Pfaffenberger, T. Afonyushkin, V. N. Bochkov, G. Maurer, K. Huber, and J. Wojta The inflammatory cytokine oncostatin M induces PAI-1 in human vascular smooth muscle cells in vitro via PI 3-kinase and ERK1/2-dependent pathways Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1962 - H1968. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
