Faculty Collaboration Database

Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. Am J Physiol Heart Circ Physiol 2008 Feb;294(2):H724-35

Date

12/07/2007

Pubmed ID

18055514

Pubmed Central ID

PMC2443685

DOI

10.1152/ajpheart.00979.2007

Scopus ID

2-s2.0-39149128273 (requires institutional sign-in at Scopus site)   162 Citations

Abstract

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 microM 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.

Author List

Dhanasekaran A, Gruenloh SK, Buonaccorsi JN, Zhang R, Gross GJ, Falck JR, Patel PK, Jacobs ER, Medhora M

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Annexin A5
Apoptosis
Benzimidazoles
Blotting, Western
Caspase 3
Caspase 9
Cell Hypoxia
Cell Line
Cell Survival
Cells, Cultured
Eicosanoids
Fluorescent Antibody Technique
Fluorescent Dyes
Myocytes, Cardiac
Phosphatidylinositol 3-Kinases
Phosphorylation
Rats
Rats, Sprague-Dawley
Signal Transduction
Tetrazolium Salts
Thiazoles
X-Linked Inhibitor of Apoptosis Protein
bcl-X Protein