Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 294, Issue 2, Pages H724-H735Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00979.2007
Keywords
caspase; ischemia; rat; mouse; fatty acids
Funding
- NHLBI NIH HHS [R01 HL068627-05, R01 HL049294, R01 HL049294-13, HL-069996, R01 HL068627, R01 HL069996-04, R01 HL069996, HL-49294] Funding Source: Medline
- NIGMS NIH HHS [R01 GM031278-24, GM-31278, R01 GM031278] Funding Source: Medline
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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 mu M 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.
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