Protective actions of epoxyeicosatrienoic acid: Dual targeting of cardiovascular PI3K and KATP channels

Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (K-ATP) channels (sarcolemmal and mitochondrial), calciumactivated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K).Wetested if EETs protect human atrial tissue ex vivo from hypoxia/reoxyge nation (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 K-ATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the K-ATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclarmide, simultaneous activation of at least 2 pathways, PI3K and K-ATP 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 K-ATP channels. (C) 2009 Elsevier Inc All rights reserved.