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Title:   Author  item
                                            SEUBERT, JOHN - NIEHS/NIH INTRAMURALitem
                                            SINAL, CHRISTOPHER - UC DALHOUSIE, PHARMACOLOGitem
                                            GRAVES, JOAN - NIEHA/NIH INTRAMURALitem
                                            DEGRAFF, LAURA - NIEHS/NIH INTRAMURALitem
                                            BRADBURY, ALYCE - NIEHS/NIH INTRAMURALitem
                                            LEE, CRAIG - N.C. SCHOOL OF PHARMACYitem
                                            GORALSKI, KERRY - UC DALHOUSIE, PHARMACOLOGitem
                                            CAREY, MICHELLE - NIEHS/NIH INTRAMURALitem
                                            LURIA, AYALA - UCD DEPT. ENTOMOLOGYitem
                                            Newman, Johnitem
                                            HAMMOCK, BRUCE - UCD DEPT. ENTOMOLOGYitem
                                            ROBERTS, HOLLY - DUKE UNIV. MED. CNT.item
                                            ROCKMAN, HOWARD - DUKE UNIV. MED. CNT.item
                                            MURPHY, ELIZABETH - NIEHS/NIH INTRAMURALitem
                                            ZELDIN, DARRLY - NIEHS/NIH INTRAMURAL
  Submitted to: Journal of Clinical Investigation
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 6/13/2006
                                    Publication  Date: 7/11/2006
                                    Citation: Seubert, J.M., Sinal, C.J., Graves, J.P., Degraff, L.M., Bradbury, A.J., Lee, C.R., Goralski, K.B., Carey, M.A., Luria, A., Newman, J.W., Hammock, B.D., Roberts, H., Rockman, H.A., Murphy, E., Zeldin, D.C. 2006. Role of soluble epoxide hydrolase in post-ischemic recovery of heart contractile function. Journal of Clinical Investigation. 2006. 99:442-450.Interpretive Summary: Epoxides produced from arachidonic acid are important regulators of cardiac function that are degraded by the soluble epoxide hydrolase (sEH) to inactive diols. Based on this knowledge, we designed experiments to explore the functional role of the sEH in the heart using the sEH knockout mice as a model. These animals have undetectable amounts of sEH in their hearts and cannot convert lipid epoxides to diols. While basal cardiac function is normal, both plasma and heart cell cultures showed greater epoxide:diol ratios in the sEH-null animals when compared to their wild type counterparts. The sEH-null hearts showed improved recovery from an ischemic stress, a sustained oxygen restriction to the heart similar to that occurring in a heart attack, but inhibitors which prevented epoxy fatty acid formation abolished the protective effect in the sEH-null animals. Treatment with a number of additional chemicals which disrupt the function of specific cellular proteins indicated that the elevated epoxy fatty acids produced their protective effects by activating a specific signaling pathway involving phosphatidylinositol-3 kinase and ATP sensitive potassium channels. Taken together, these results suggest that manipulating sEH activity may represent a novel therapeutic approach to management of ischemic heart disease in humans.
                                Technical Abstract: Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). To examine the functional role of sEH in the heart, mice with targeted disruption of the Ephx2 gene were studied. Hearts from sEH null mice have undetectable levels of sEH mRNA and protein, and cannot convert EETs to DHETs. sEH null mice have normal heart anatomy and basal contractile function, but have higher fatty acid epoxide:diol ratios in plasma and cardiomyocyte cell culture media compared to wild type (WT). sEH null hearts have improved recovery of left ventricular developed pressure (LVDP) compared to WT hearts following 20min ischemia and 40min reperfusion. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10-100 nM) for 20min prior to ischemia abolishes this cardioprotective phenotype. Inhibitor studies demonstrate that perfusion with phosphatidylinositol-3 kinase (PI3K) inhibitors wortmannin (200nM) or LY294002 (5'M), the ATP-sensitive K+ channel (KATP) inhibitor glibenclamide (1'M), or the mitochondrial KATP (mitoKATP) inhibitor 5-hydroxydecanoate (100-200'M) abolishes the cardioprotection in sEH null hearts. Consistent with increased activation of the PI3K cascade, sEH null mice exhibit increased cardiac expression of glycogen synthase kinase-3' (GSK-3') phospho-protein following ischemia. Together, these data suggest that targeted disruption of sEH increases the availability of cardioprotective EETs that work by activating PI3K signaling pathways and KATP channels.


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