Résumé
Aims: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that have known cardioprotective properties. While the mechanism(s) remains unknown, evidence suggests that phosphoinositide 3-kinase (PI3K) and sarcolemmal ATP-sensitive potassium channels (pmK ATP) are important. However the role of specific PI3K isoforms and corresponding intracellular mechanisms remains unknown. Methods and results: To study this, mice hearts were perfused in Langendorff mode for 40min of baseline and subjected to 20 or 30min of global no-flow ischemia followed by 40min of reperfusion. C57BL6 mice perfused with 11,12-EET (1μM) had improved postischemic recovery, whereas co-perfusion with PI3Kα inhibitor, PI-103 (0.1μM), abolished the EET-mediated effect. In contrast, blocking of PI3Kβ or PI3Kγ isoforms failed to inhibit EET-mediated cardioprotection. In addition to the improved post-ischemic recovery, increased levels of p-Akt, decreased calcineurin activity and decreased translocation of proapoptotic protein BAD to mitochondria were noted in EET-treated hearts. Perfusion of 11,12-EET to Kir6.2 deficient mice (pmK ATP) failed to improve postischemic recovery, decrease calcineurin activity and translocation of proapoptotic protein BAD, however increased levels of p-Akt were still observed. Patch-clamp experiments demonstrated that 11,12-EET could not activate pmK ATP currents in myocytes pre-treated with PI-103. Mechanistic studies in H9c2 cells demonstrate that 11,12-EET limits anoxia-reoxygenation triggered Ca 2+ accumulation and maintains mitochondrial δΨm compared to controls. Both PI-103 and glibenclamide (10μM, pmK ATP inhibitor) abolished EET cytoprotection. Conclusion: Together our data suggest that EET-mediated cardioprotection involves activation of PI3Kα, upstream of pmK ATP, which prevents Ca 2+ overload and maintains mitochondrial function.
Langue d'origine | English |
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Pages (de-à) | 43-52 |
Nombre de pages | 10 |
Journal | Journal of Molecular and Cellular Cardiology |
Volume | 53 |
Numéro de publication | 1 |
DOI | |
Statut de publication | Published - juill. 2012 |
Publié à l'externe | Oui |
Note bibliographique
Funding Information:JMS is the recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada, a Health Scholar Award from the Alberta Innovates Health Solutions (AIHS). This work was supported by operating grants from Heart and Stroke Foundation of Canada (JMS) and the Canadian Institutes of Health Research (JMS, MOP 15037, PEI, MOP 67160). PEL received salary support as an AIHS Senior Scholar and holds the Dr. Charles A. Allard Chair in Diabetes Research.
ASJC Scopus Subject Areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't