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Protection of mouse pulmonary arteries from hypoxia‐induced apoptosis: Cross talk between phosphoinositide 3‐kinase (PI3K) and ATP‐sensitive potassium (KATP) channels
Author(s) -
Bodiga Sreedhar,
Falck John R,
Zhang Rong,
Gao Ying,
Jacobs Elizabeth R,
Medhora Meetha M
Publication year - 2008
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.22.1_supplement.915.2
Subject(s) - wortmannin , pinacidil , diazoxide , epoxygenase , potassium channel , atp sensitive potassium channel , apoptosis , pharmacology , epoxyeicosatrienoic acid , glibenclamide , pi3k/akt/mtor pathway , chemistry , hypoxic pulmonary vasoconstriction , hypoxia (environmental) , endocrinology , medicine , arachidonic acid , vasoconstriction , biochemistry , enzyme , organic chemistry , oxygen , diabetes mellitus , insulin
We have demonstrated that epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, inhibit both intrinsic and extrinsic pathways of apoptosis of human endothelial cells, through activation of phosphatidyl inositol 3‐kinase (PI3K). EETs are also potent sarcolemmal and mitochondrial ATP‐sensitive K + (KATP) channel activators. In this study, we examined the effects of EETs on hypoxia/reoxygenation (HR)‐induced apoptosis (as determined by measuring increase in caspase 3 activity) in mouse pulmonary arteries maintained ex vivo, by organ culture. Mouse pulmonary arteries subjected to HR for 8/16 h demonstrated increased apoptosis. This was inhibited by pretreatment with either 14,15‐EET (300 nM), the non‐specific KATP channel opener pinacidil (100 microM) or the mitochondrial KATP channel opener, diazoxide (100 microM). Pretreatment with the PI3K inhibitor, wortmannin abolished the protective effect of EET, pinacidil or diazoxide. There was no cumulative effect of wortmannin and glibenclamide when applied together, on the apoptotic indices during HR. Thus, cross‐talk between PI3K and KATP channels, two targets of signaling by EET, mediate protection of the pulmonary vasculature. Funding: NIH/NHLBI 69996 (MMM), 68627 (ERJ), 49294 (ERJ), GM 31278 (JRF).