TY - JOUR
T1 - Protective actions of epoxyeicosatrienoic acid
T2 - Dual targeting of cardiovascular PI3K and KATP channels
AU - Bodiga, Sreedhar
AU - Zhang, Rong
AU - Jacobs, Dexter E.
AU - Larsen, Brandon T.
AU - Tampo, Akihito
AU - Manthati, Vijay L.
AU - Kwok, Wai Meng
AU - Zeldin, Darryl C.
AU - Falck, John R.
AU - Gutterman, David D.
AU - Jacobs, Elizabeth R.
AU - Medhora, Meetha M.
N1 - Funding Information:
We thank all members of the laboratories of ERJ and MMM for their help and the Division of Cardiothoracic Surgery at the Medical College of Wisconsin, the Cardiothoracic Surgery Group of Milwaukee, the Cardiovascular Surgery Associates of Milwaukee, the Midwest Heart Surgery Institute, and the Wisconsin Heart Group for providing surgical specimens. Financial support was provided by NIH Grants HL069996 (M Medhora), HL49294 (ER Jacobs), HL68627 (ER Jacobs), HL-68769 (DD Gutterman), GM 31278 (JR Falck), Veterans Affairs Merit Award (DD Gutterman), American Heart Association (BT Larsen) and the Robert A.Welch Foundation (JR Falck). This research was also supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (DC Zeldin).
PY - 2009/6
Y1 - 2009/6
N2 - 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.
AB - 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.
KW - Epoxide hydrolase
KW - Human myocardium
KW - Hypoxia/reoxygenation
KW - Lactate dehydrogenase release
KW - Mitochondrial membrane potential
KW - Pulmonary artery
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U2 - 10.1016/j.yjmcc.2009.01.009
DO - 10.1016/j.yjmcc.2009.01.009
M3 - Article
C2 - 19336274
AN - SCOPUS:67349200006
SN - 0022-2828
VL - 46
SP - 978
EP - 988
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -