Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice

• Published in: Prostaglandins & other lipid mediators 2013-07, Vol.104-105, p.8-17
• Main Authors: Chaudhary, Ketul R., Zordoky, Beshay N.M., Edin, Matthew L., Alsaleh, Nasser, El-Kadi, Ayman O.S., Zeldin, Darryl C., Seubert, John M.
• Format: Article
• Language: English
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - metabolism; 8,11,14-Eicosatrienoic Acid - pharmacology; Age Factors; Aging; Animals; Benzoates - pharmacology; Cardiotonic Agents - pharmacology; Cells, Cultured; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - deficiency; Epoxyeicosatrienoic acids; Female; Gene Expression Regulation; Heart - drug effects; Heart - physiopathology; Ischemia reperfusion injury; Leukotoxin diol; Male; Mice; Mice, Knockout; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Organ Culture Techniques; Oxidative Stress; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Soluble epoxide hydrolase inhibitor; Stearic Acids - metabolism; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2012.08.001

► Young and aged sEH null mice are protected against ischemia reperfusion injury. ► Aging causes loss of cardioprotection in aged CYP2J2 Tr mice that can be prevented by inhibition of sEH. ► Aging does not affect epoxide hydrolase activity in mouse hearts. ► Loss of cardioprotection in aged CYP2J2 Tr mice is due to increased levels of DiHOME, oxidative stress and decreased PP2A activation. ► EETs improve left ventricular functional recovery following ischemia-reperfusion injury in aged mice. Cardioprotective effects of epoxyeicosatrienoic acids (EETs) have been demonstrated in models of young mice with either the cardiomyocyte specific over-expression of cytochrome P450 2J2 (CYP2J2 Tr) or deletion of soluble epoxide hydrolase (sEH null). In this study we examined differences in EET-induced cardioprotection in young (2 months) and aged (12 months) CYP2J2 Tr and sEHnull mice using Langendorff isolated perfused heart model. Improved postischemic functional recovery was observed in both young and aged sEH null mice compared to age matched WT. Conversely, the cardioprotective effect observed in young CYP2J2 Tr was lost in aged CYP2J2 Tr mice. The loss of cardioprotection in aged CYP2J2 Tr was regained following perfusion with the sEH inhibitor t-AUCB. Data demonstrated increased levels of leukotoxin diol (DiHOME) and oxidative stress as well decreased protein phosphatase 2A (PP2A) activation in aged CYP2J2 Tr. In conclusion, inhibition of sEH and EET-induced cardioprotection is maintained in aged mice. However, the loss of protective effects observed in aged CYP2J2 Tr might be attributed to increased levels of DiHOME, oxidative stress and/or decreased PP2A activity.