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

Zhiping Cao, Lijuan Liu, William Packwood, Matthias Merkel, Patricia D. Hurn, Donna M. Van Winkle

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number1
DOIs
StatePublished - Jan 2008

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Phosphatidylinositol 3-Kinase
Enkephalins
Sex Characteristics
Cardiac Myocytes
Propidium
Collagenases
Epidermal Growth Factor Receptor
Small Interfering RNA
Transcriptional Activation
Digestion
Protein Isoforms
Cell Death
Maintenance
Pharmacology

Keywords

  • Intracellular signaling
  • Opioid
  • Peptides
  • Pharmacological preconditioning

ASJC Scopus subject areas

  • Physiology

Cite this

Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection : Role of PI3K/Akt. / Cao, Zhiping; Liu, Lijuan; Packwood, William; Merkel, Matthias; Hurn, Patricia D.; Van Winkle, Donna M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 1, 01.2008.

Research output: Contribution to journalArticle

Cao, Zhiping ; Liu, Lijuan ; Packwood, William ; Merkel, Matthias ; Hurn, Patricia D. ; Van Winkle, Donna M. / Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection : Role of PI3K/Akt. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 294, No. 1.
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