Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart

Matthew L. Edin, ZhongJing Wang, J. Alyce Bradbury, Joan P. Graves, Fred B. Lih, Laura M. DeGraff, Julie F. Foley, Robert Torphy, Oline Ronnekleiv, Kenneth B. Tomer, Craig R. Lee, Darryl C. Zeldin

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (αMHC-CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte- vs. endothelial-derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 Tr and Tie2-CYP2J2 Tr) or EET hydrolysis (Tie2-sEH Tr). Compared to wild-type (WT), αMHC-CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2-CYP2J2 Tr and Tie2-sEH Tr hearts. Surprisingly, compared to WT, Tie2-CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14%) and increased infarct size after I/R (from 51 to 61%). Tie2-CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2-CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10-DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31%, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.

Original languageEnglish (US)
Pages (from-to)3436-3447
Number of pages12
JournalFASEB Journal
Volume25
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Reperfusion Injury
Cytochrome P-450 Enzyme System
Ventricular Pressure
Recovery
Reactive Oxygen Species
Cardiac Myocytes
Reperfusion
Ischemia
Acids
Cytochrome P-450 CYP2C8
Biosynthesis
Masks
Arachidonic Acid
Transgenic Mice
arachidonate epoxygenase
Hydrolysis
Protein Isoforms

Keywords

  • CYP2J2
  • EETs
  • Langendorff
  • Leukotoxin
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Edin, M. L., Wang, Z., Bradbury, J. A., Graves, J. P., Lih, F. B., DeGraff, L. M., ... Zeldin, D. C. (2011). Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. FASEB Journal, 25(10), 3436-3447. https://doi.org/10.1096/fj.11-188300

Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. / Edin, Matthew L.; Wang, ZhongJing; Bradbury, J. Alyce; Graves, Joan P.; Lih, Fred B.; DeGraff, Laura M.; Foley, Julie F.; Torphy, Robert; Ronnekleiv, Oline; Tomer, Kenneth B.; Lee, Craig R.; Zeldin, Darryl C.

In: FASEB Journal, Vol. 25, No. 10, 10.2011, p. 3436-3447.

Research output: Contribution to journalArticle

Edin, ML, Wang, Z, Bradbury, JA, Graves, JP, Lih, FB, DeGraff, LM, Foley, JF, Torphy, R, Ronnekleiv, O, Tomer, KB, Lee, CR & Zeldin, DC 2011, 'Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart', FASEB Journal, vol. 25, no. 10, pp. 3436-3447. https://doi.org/10.1096/fj.11-188300
Edin, Matthew L. ; Wang, ZhongJing ; Bradbury, J. Alyce ; Graves, Joan P. ; Lih, Fred B. ; DeGraff, Laura M. ; Foley, Julie F. ; Torphy, Robert ; Ronnekleiv, Oline ; Tomer, Kenneth B. ; Lee, Craig R. ; Zeldin, Darryl C. / Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. In: FASEB Journal. 2011 ; Vol. 25, No. 10. pp. 3436-3447.
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abstract = "Cytochrome P450 (CYP) epoxygenases CYP2C8 and CYP2J2 generate epoxyeicosatrienoic acids (EETs) from arachidonic acid. Mice with expression of CYP2J2 in cardiomyocytes (αMHC-CYP2J2 Tr) or treated with synthetic EETs have increased functional recovery after ischemia/reperfusion (I/R); however, no studies have examined the role of cardiomyocyte- vs. endothelial-derived EETs or compared the effects of different CYP epoxygenase isoforms in the ischemic heart. We generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 Tr and Tie2-CYP2J2 Tr) or EET hydrolysis (Tie2-sEH Tr). Compared to wild-type (WT), αMHC-CYP2J2 Tr hearts showed increased recovery of left ventricular developed pressure (LVDP) and decreased infarct size after I/R. In contrast, LVDP recovery and infarct size were unchanged in Tie2-CYP2J2 Tr and Tie2-sEH Tr hearts. Surprisingly, compared to WT, Tie2-CYP2C8 Tr hearts had significantly reduced LVDP recovery (from 21 to 14{\%}) and increased infarct size after I/R (from 51 to 61{\%}). Tie2-CYP2C8 Tr hearts also exhibited increased reactive oxygen species (ROS) generation, dihydroxyoctadecenoic acid (DiHOME) formation, and coronary resistance after I/R. ROS scavengers and CYP2C8 inhibition reversed the detrimental effects of CYP2C8 expression in Tie2-CYP2C8 Tr hearts. Treatment of WT hearts with 250 nM 9,10-DiHOME decreased LVDP recovery compared to vehicle (16 vs. 31{\%}, respectively) and increased coronary resistance after I/R. These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R.",
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AU - DeGraff, Laura M.

AU - Foley, Julie F.

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