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Enhanced Postischemic Functional Recovery in CYP2J2 Transgenic Hearts Involves Mitochondrial ATP-Sensitive K + Channels and p42/p44 MAPK Pathway
Open accessAbstract
Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N -methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K + channel (K ATP ) inhibitor glibenclamide (GLIB) or the mitochondrial K ATP (mitoK ATP ) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK ATP activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 μmol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase (MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK ATP and p42/p44 MAPK.
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Cites
Ardehali, H., Chen, Z., Ko, Y., Mejía-Alvarez, R., & Marbán, E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401703101 · Cited by 215
Cited by
Action of epoxyeicosatrienoic acids on cellular function
Spector, A. A., & Norris, A. W. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00402.2006 · Cited by 477
Epoxides and Soluble Epoxide Hydrolase in Cardiovascular Physiology
Imig, J. D. (2012) · Physiological Reviews · doi:10.1152/physrev.00021.2011 · Cited by 365
Imig, J. D., Zhao, X., Zaharis, C. Z., Olearczyk, J. J., Pollock, D. M., Newman, J. W., Kim, I.-H., Watanabe, T., & Hammock, B. D. (2005) · Hypertension · doi:10.1161/01.hyp.0000176237.74820.75 · Cited by 257
Self-citationRole of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids
Konkel, A., & Schunck, W.-H. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2010.09.009 · Cited by 227
Cytochrome P450–dependent metabolism of ω-6 and ω-3 long-chain polyunsaturated fatty acids
Arnold, C., Konkel, A., Fischer, R., & Schunck, W.-H. (2010) · Pharmacological Reports · doi:10.1016/s1734-1140(10)70311-x · Cited by 174
Metadata
- Authors
- Seubert, J., Yang, B., Bradbury, J. A., Graves, J., Degraff, L. M., Gabel, S., Gooch, R., Foley, J., Newman, J., Mao, L., Rockman, H. A., Hammock, B. D., Murphy, E., & Zeldin, D. C.
- Venue
- Circulation Research
- Published
- 2004-09-03
- Volume
- 95
- Issue
- 5
- Pages
- 506-514
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2163127729
- Cited by
- 273
- References
- 1
- FWCI
- 12.47
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Seubert, J., Yang, B., Bradbury, J. A., Graves, J., Degraff, L. M., Gabel, S., Gooch, R., Foley, J., Newman, J., Mao, L., Rockman, H. A., Hammock, B. D., Murphy, E., & Zeldin, D. C. (2004). Enhanced Postischemic Functional Recovery in CYP2J2 Transgenic Hearts Involves Mitochondrial ATP-Sensitive K + Channels and p42/p44 MAPK Pathway. Circulation Research. https://doi.org/10.1161/01.res.0000139436.89654.c8
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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