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Epoxyeicosatrienoic acids (EETs) block cardiomyocyte cell death from hypoxia/reoxygenation injury via the PI3K/Akt survival pathway
Author(s) -
Dhanasekaran Anuradha,
Gruenloh Stephanie,
Zhang Rong,
Gross Garrett,
Falck John,
Jacobs Elizabeth,
Medhora Meetha
Publication year - 2007
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.21.6.a1288-c
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , xiap , myocyte , apoptosis , hypoxia (environmental) , chemistry , gsk 3 , programmed cell death , microbiology and biotechnology , pharmacology , kinase , biology , caspase , biochemistry , organic chemistry , oxygen
EETs attenuate ischemia/reperfusion (IR) injury to the heart in animal models. Cell death by apoptosis is commonly observed in cardiac myocytes after IR injury in rodents and humans. We hypothesized that EETs protect cardiomyocytes from apoptosis by IR, via stimulation of the phosphoinositide 3‐kinase (PI3K)/Akt survival pathway. To test this we used immortalized cells from a mouse atrial lineage (HL‐1) and primary myocytes derived from neonatal rat hearts. Pretreatment with EETs (14,15−, 11,12−, 8,9− but not 5,6‐EET) attenuated apoptosis after exposure to hypoxia/reoxygenation (HR, 8 hours hypoxia in the presence of 10 mM deoxyglucose, followed by 16 hours of reoxygenation). EETs activated PI3K and phosphorylated Akt. Myocytes pretreated with EETs and exposed to HR demonstrated increase in phosphorylation of BAD (Bcl‐xL/Bcl‐2 associated death promoter) and GSK3beta (glycogen synthase kinase 3beta), inhibition of caspase 9 activity and increase in expression of XIAP (X‐linked inhibitor of apoptosis), when compared to vehicle‐treated controls. We therefore identify six intermediates of the PI3K/Akt pathway that participate in EET‐mediated survival, defining a mechanism for cardiac protection by EETs. Supported by NHLBI 69996, 68627, 49294 and GM 31278.