HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/H302    most recent 00845.2007v1 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 Web of Science 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 Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Cao, Z. Articles by Van Winkle, D. M. Search for Related Content PubMed PubMed Citation Articles by Cao, Z. Articles by Van Winkle, D. M.

Sex differences in the mechanism of Met⁵-enkephalin-induced cardioprotection: role of PI3K/Akt

¹Research and ²Anesthesiology Services, Veterans Affairs Medical Center; and ³Department of Anesthesiology, Oregon Health and Sciences University, Portland, Oregon

Submitted 19 July 2007 ; accepted in final form 30 October 2007

Met⁵-enkephalin (ME)-induced cardioprotection occurs via epidermal growth factor receptor (EGFR) transactivation with the subsequent activation of phosphatidylinositol 3-kinase (PI3K). In the present study, we investigated whether there is a sex difference in ME-elicited PI3K signaling. Neonatal murine cardiomyocytes were isolated by collagenase digestion and subjected to 90 min hypoxia and 180 min reoxygenation at 37°C (n = 5 to 7 replicates). PI3K/Akt signaling was interrogated using pharmacological inhibitors and small interfering RNA (siRNA). Cell death was assessed by propidium iodide. More than 300 cells were examined for each treatment. The data are presented as means ± SE. There was not a sex difference in the basal content of total Akt. ME (100 µM) elicited comparable protection in both sexes. Wortmannin and the nonselective Akt inhibitor IV completely abolished ME-induced protection in male cardiomyocytes but only attenuated protection in female cardiomyocytes. Isoform-selective knockdown of Akt in males with siRNAs against Akt1/2 completely abolished ME-induced cardioprotection, whereas the siRNAs against Akt3 only attenuated protection of 40%. In contrast, in females the siRNAs against Akt1/2 attenuated and against Akt3 eliminated ME-induced cardioprotection. There is not a sex difference in the degree of ME-induced protection, and there is a sex difference in the cardioprotective signaling pathways after the administration of ME; ME-induced cardioprotection in males primarily utilizes a PI3K/Akt1/2 pathway and in females primarily utilizes a PI3K/Akt3 pathway. The incomplete loss of protection in females following the blockade of PI3K suggests that additional factors may facilitate the maintenance or function of activated Akt.

peptides; opioid; pharmacological preconditioning; intracellular signaling

This article has been cited by other articles:

				B. Ostadal, I. Netuka, J. Maly, J. Besik, and I. Ostadalova Gender Differences in Cardiac Ischemic Injury and Protection--Experimental Aspects Experimental Biology and Medicine, September 1, 2009; 234(9): 1011 - 1019. [Abstract] [Full Text] [PDF]

				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]