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1 Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Biochemistry, UT Southwestern Medical Center at Dallas, Dallas, Texas, United States
4 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: medhoram{at}mcw.edu.
Epoxyeicosatrienoic acids (EETs) reduce infarction of the myocardium after ischemia/reperfusion injury to rodent and dog hearts mainly by opening sarcolemmal and mitochondrial potassium channels. Other mediators for the action of EET have been proposed though no definitive pathway or mechanism has yet been reported. Using cultured cells from two rodent species, immortalized myocytes from a mouse atrial lineage (HL-1) and primary myocytes derived from neonatal rat hearts, we observed that pretreatment with EETs (1 µM of 14,15-, 11,12-, or 8,9-EET) attenuates apoptosis after exposure to hypoxia/reoxygenation (HR). EETs also preserved functional beating of neonatal myocytes in culture after exposure to HR. We demonstrated that EETs increased activity of the pro-survival enzyme phosphoinositide 3 kinase (PI3K). In fact cardiomyocytes pretreated with EET and exposed to HR exhibited anti-apoptotic changes in at least five downstream effectors of PI3K: Akt, BAD (Bcl-xL/Bcl-2 associated death promoter), caspase 9 and 3 activities and expression of XIAP (X-linked inhibitor of apoptosis), when compared to vehicle-treated controls. The PI3K/Akt pathway is one of the strongest intracellular pro-survival signaling systems. Our studies show that EETs regulate multiple molecular effectors of this pathway. Understanding the targets of action of EET-mediated protection will promote development of these fatty acids as therapeutic agents against cardiac ischemia/reperfusion.
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