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The Role of PI3K Isoforms and Sarcolemmal KATP Channel in Epoxyeicosatrienoic Acid Mediated Cardioprotection
Author(s) -
Batchu Sri Nagarjun,
ElSikhry Haitham,
Chaudhary Ketul R,
Light Peter,
Oudit Gavin,
Seubert John M
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1085.7
Subject(s) - cardioprotection , epoxyeicosatrienoic acid , epoxygenase , chelerythrine , cytoprotection , pharmacology , chemistry , mitochondrion , gene isoform , diacylglycerol kinase , intracellular , diazoxide , arachidonic acid , protein kinase c , microbiology and biotechnology , medicine , ischemia , biology , biochemistry , apoptosis , phosphorylation , enzyme , insulin , gene
Epoxyeicosatrienoic acids (EET) are cytochrome P450 epoxygenase metabolites of arachidonic acid that have cardioprotective effects. Our objective was to investigate the role of PI3K isoforms in EET‐mediated cardioprotection. Hearts from mice were perfused using a Langendorff apparatus to assess recovery of function following ischemia‐reperfusion. The PI3Kalpha inhibitor PI‐103 (0.1μM) abolished 11,12‐EET mediated improved postischemic recovery, while the PI3Kbeta inhibitor TGX‐221 (1μM) or hearts from PI3Kgamma (−/−) mice failed to block EET‐mediated cardioprotection, suggesting the key isoform involved is PI3Kalpha. Increased expression pAkt, decreased calcineurin activity and decreased translocation of proapoptotic protein BAD to mitochondria were observed in hearts treated with 11,12‐EET. Hearts from pmKATP deficient mice did not respond to EET‐mediated improved postischemic recovery however increased expression of pAkt was observed. H9c2 cells treated with 11,12‐EET had reduced intracellular Ca2+ accumulation and maintained mitochondrial function compared to controls following anoxia‐reoxygenation. Both PI‐103 (0.1μM) and glibenclamide (10μM pmKATP inhibitor) abolished EET cytoprotection. Together our data suggests EET mediated cardioprotection involves PI3Kalpha activation, upstream of pmKATP, which prevents Ca2+ overload and maintaining mitochondrial function.