title: Novel Roles of Epoxyeicosanoids in Regulating Cardiac Mitochondria.
abstract: Maintenance of a healthy pool of mitochondria is important for the function and survival of terminally differentiated cells such as cardiomyocytes. Epoxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of arachidonic acid by cytochrome P450 epoxygenases. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. The aim of this study was to investigate whether EET-mediated effects influence mitochondrial quality in HL-1 cardiac cells during starvation. HL-1 cells were subjected to serum- and amino acid free conditions for 24h. We employed a dual-acting synthetic analog UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET molecules. We demonstrated that EET-mediated events significantly improved mitochondrial function as assessed by preservation of the ADP/ATP ratio and oxidative respiratory capacity. Starvation induced mitochondrial hyperfusion observed in control cells was attenuated by UA-8. However, EET-mediated events did not affect the expression of mitochondrial dynamic proteins Fis1, DRP-1 or Mfn2. Rather we observed increased levels of OPA-1 oligomers and increased mitochondrial cristae density, which correlated with the preserved mitochondrial function. Increased DNA binding activity of pCREB and Nrf1/2 and increased SIRT1 activity together with elevated mitochondrial proteins suggest EET-mediated events led to preserved mitobiogenesis. Thus, we provide new evidence for EET-mediated events that preserve a healthier pool of mitochondria in cardiac cells following starvation-induced stress.
authors: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors: Haitham E
authors: HE
authors: El-Sikhry
authors: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors: Nasser
authors: N
authors: Alsaleh
authors: Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors: Rambabu
authors: R
authors: Dakarapu
authors: Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors: John R
authors: JR
authors: Falck
authors: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.|Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors: John M
authors: JM
authors: Seubert
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: C558111:(13-(3-propylureido)tridec-8-enoic acid); C494022:14,15-eicosa-5-enoic acid; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D009829:Oleic Acids; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D000154:Aconitate Hydratase; D015126:8,11,14-Eicosatrienoic Acid