Protective actions of epoxyeicosatrienoic acid: dual targeting of cardiovascular PI3K and KATP channels. J Mol Cell Cardiol 2009 Jun;46(6):978-88
Date
04/02/2009Pubmed ID
19336274Pubmed Central ID
PMC2796716DOI
10.1016/j.yjmcc.2009.01.009Scopus ID
2-s2.0-67349200006 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2-/-) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.
Author List
Bodiga S, Zhang R, Jacobs DE, Larsen BT, Tampo A, Manthati VL, Kwok WM, Zeldin DC, Falck JR, Gutterman DD, Jacobs ER, Medhora MMAuthor
Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAndrostadienes
Animals
Animals, Newborn
Caspase 3
Cells, Cultured
Electrophysiology
Enzyme Activation
Female
Glyburide
Humans
In Situ Nick-End Labeling
In Vitro Techniques
KATP Channels
Male
Membrane Potential, Mitochondrial
Mice
Myocardial Reperfusion Injury
Myocardium
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Rats
Rats, Sprague-Dawley
