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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H724    most recent 00979.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Dhanasekaran, A. Articles by Medhora, M. Search for Related Content PubMed PubMed Citation Articles by Dhanasekaran, A. Articles by Medhora, M.

Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia

¹Division of Pulmonary and Critical Care Medicine, Cardiovascular Research Center, and ²Department of Pharmacology and Toxicology, ³Medical College of Wisconsin, Milwaukee, Wisconsin; and ⁴Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 23 August 2007 ; accepted in final form 28 November 2007

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, although 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) attenuated apoptosis after exposure to hypoxia and reoxygenation (H/R). EETs also preserved the functional beating of neonatal myocytes in culture after exposure to H/R. We demonstrated that EETs increased the activity of the prosurvival enzyme phosphatidylinositol 3-kinase (PI3K). In fact, cardiomyocytes pretreated with EET and exposed to H/R exhibited antiapoptotic changes in at least five downstream effectors of PI3K, protein kinase B (Akt), Bcl-x_L/Bcl-2-associated death promoter, caspases-9 and -3 activities, and the expression of the X-linked inhibitor of apoptosis, compared with vehicle-treated controls. The PI3K/Akt pathway is one of the strongest intracellular prosurvival 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 the development of these fatty acids as therapeutic agents against cardiac ischemia-reperfusion.

caspase; ischemia; rat; mouse; fatty acids

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