TY - JOUR
T1 - Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia
AU - Dhanasekaran, Anuradha
AU - Gruenloh, Stephanie K.
AU - Buonaccorsi, J. Noelle
AU - Zhang, Rong
AU - Gross, Garrett J.
AU - Falck, J R
AU - Patel, Paresh K.
AU - Jacobs, Elizabeth R.
AU - Medhora, Meetha
PY - 2008/2
Y1 - 2008/2
N2 - 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-xL/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.
AB - 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-xL/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.
KW - Caspase
KW - Fatty acids
KW - Ischemia
KW - Mouse
KW - Rat
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U2 - 10.1152/ajpheart.00979.2007
DO - 10.1152/ajpheart.00979.2007
M3 - Article
C2 - 18055514
AN - SCOPUS:39149128273
SN - 0363-6135
VL - 294
SP - H724-H735
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2
ER -