Mechanisms by which epoxyeicosatrienoic acids (EETs) elicit cardioprotection in rat hearts

Abstract Cytochrome P450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce reductions in infarct size in canine myocardium following ischemia–reperfusion injury via opening of either the sarcolemmal KATP (sarcKATP ) or mi...

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Published in:	Journal of molecular and cellular cardiology 2007-03, Vol.42 (3), p.687-691
Main Authors:	Gross, Garrett J, Hsu, Anna, Falck, John R, Nithipatikom, Kasem
Format:	Article
Language:	eng
Subjects:	11,12-EET 14,15-EET 8,11,14-Eicosatrienoic Acid - analogs & derivatives 8,11,14-Eicosatrienoic Acid - therapeutic use 8,9-EET Adenosine Triphosphate - metabolism Animals Cardiovascular CYP450 Male Mito- and sarcK ATP channels Myocardial Infarction - drug therapy Myocardial Infarction - pathology Potassium Channels - metabolism Rats Rats, Sprague-Dawley Reactive oxygen species Regional Blood Flow - drug effects Tiopronin - toxicity
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Summary:	Abstract Cytochrome P450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce reductions in infarct size in canine myocardium following ischemia–reperfusion injury via opening of either the sarcolemmal KATP (sarcKATP ) or mitochondrial KATP (mitoKATP ) channel. In the present study, we subjected intact rat hearts to 30 min of left coronary artery occlusion and 2 h of reperfusion followed by tetrazolium staining to determine infarct size as a percent of the area at risk (IS/AAR, %). The results demonstrate that the two major regioisomers of the CYP epoxygenase pathway, 11,12-EET (2.5 mg/kg, iv) and 14,15-EET (2.5 mg/kg, iv) significantly reduced myocardial infarct size (IS/AAR, %) in rats as compared with control (41.9 ± 2.3%, 40.9 ± 1.2% versus 61.5 ± 1.6%, respectively), whereas, a third regioisomer, 8,9-EET (2.5 mg/kg, iv) had no effect (55.2 ± 1.4). The protective effect of pretreatment with 11,12- and 14,15-EETs was completely abolished (61.9 ± 0.7%, 58.6 ± 3.1%, HMR; 63.3 ± 1.2%, 63.2 ± 2.5%, 5-HD) in the presence of the selective sarcKATP channel antagonist, HMR 1098 (6 mg/kg, iv) or the selective mitoKATP channel antagonist, 5-HD (10 mg/kg, iv) given 10 min after 11,12- or 14,15-EET administration but 5 min prior to index ischemia. Furthermore, concomitant pretreatment with 11,12- or 14,15-EET in combination with the free radical scavenger, 2-mercaptopropionyl glycine (2-MPG), at a dose (20 mg/kg, iv) that had no effect on IS/AAR (57.7 ± 1.3%), completely abolished the cardioprotective effect of 11,12- and 14,15-EETs (58.2 ± 1.6%, 61.4 ± 1.0%), respectively. These data suggest that part of the cardioprotective effects of EETs in rat hearts against infarction is the result of an initial burst of reactive oxygen species (ROS) and subsequent activation of both the sarcKATP and mitoKATP channel.
ISSN:	0022-2828 1095-8584