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Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts.
Edin, Matthew L; Gruzdev, Artiom; Bradbury, J Alyce; Graves, Joan P; Lih, Fred B; DeGraff, Laura M; Fleming, Ingrid; Zeldin, Darryl C.
Afiliación
  • Edin ML; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Gruzdev A; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Bradbury JA; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Graves JP; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Lih FB; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • DeGraff LM; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Fleming I; Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
  • Zeldin DC; Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA. Electronic address: zeldin@niehs.nih.gov.
J Biol Chem ; 299(4): 103049, 2023 04.
Article en En | MEDLINE | ID: mdl-36822325
Cytochromes P450 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which have numerous effects. After cardiac ischemia, EET-induced coronary vasodilation increases delivery of oxygen/nutrients to the myocardium, and EET-induced signaling protects cardiomyocytes against postischemic mitochondrial damage. Soluble epoxide hydrolase 2 (EPHX2) diminishes the benefits of EETs through hydrolysis to less active dihydroxyeicosatrienoic acids. EPHX2 inhibition or genetic disruption improves recovery of cardiac function after ischemia. Immunohistochemical staining revealed EPHX2 expression in cardiomyocytes and some endothelial cells but little expression in cardiac smooth muscle cells or fibroblasts. To determine specific roles of EPHX2 in cardiac cell types, we generated mice with cell-specific disruption of Ephx2 in endothelial cells (Ephx2fx/fx/Tek-cre) or cardiomyocytes (Ephx2fx/fx/Myh6-cre) to compare to global Ephx2-deficient mice (global Ephx2-/-) and WT (Ephx2fx/fx) mice in expression, EET hydrolase activity, and heart function studies. Most cardiac EPHX2 expression and activity is in cardiomyocytes with substantially less activity in endothelial cells. Ephx2fx/fx/Tek-cre hearts have similar EPHX2 expression, hydrolase activity, and postischemic cardiac function as control Ephx2fx/fx hearts. However, Ephx2fx/fx/Myh6-cre hearts were similar to global Ephx2-/- hearts with significantly diminished EPHX2 expression, decreased hydrolase activity, and enhanced postischemic cardiac function compared to Ephx2fx/fx hearts. During reperfusion, Ephx2fx/fx/Myh6-cre hearts displayed increased ERK activation compared to Ephx2fx/fx hearts, which could be reversed by EEZE treatment. EPHX2 did not regulate coronary vasodilation in this model. We conclude that EPHX2 is primarily expressed in cardiomyocytes where it regulates EET hydrolysis and postischemic cardiac function, whereas endothelial EPHX2 does not play a significant role in these processes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Miocitos Cardíacos / Miocardio Límite: Animals Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Miocitos Cardíacos / Miocardio Límite: Animals Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos