Circulation Research. 2004;95:506-514
Published online before print July 15, 2004, doi: 10.1161/01.RES.0000139436.89654.c8
Published online before print July 15, 2004, doi: 10.1161/01.RES.0000139436.89654.c8
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Enhanced Postischemic Functional Recovery in CYP2J2 Transgenic Hearts Involves Mitochondrial ATP-Sensitive K+ Channels and p42/p44 MAPK Pathway
From the Division of Intramural Research (J.S., B.Y., J.A.B., J.G., L.M.D, S.G., R.G., J.F., E.M., D.C.Z.), NIEHS/NIH, Research Triangle Park, NC; the Department of Entomology and Cancer Research Center (J.N., B.D.H.), University of California, Davis; and the Department of Medicine (L.M., H.A.R., D.C.Z.), Duke University Medical Center, Durham, NC.
Correspondence to Darryl C. Zeldin, MD, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr, Research Triangle Park, NC 27709. E-mail zeldin{at}niehs.nih.gov
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 (KATP) inhibitor glibenclamide (GLIB) or the mitochondrial KATP (mitoKATP) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoKATP 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 mitoKATP and p42/p44 MAPK.
Key Words: arachidonic acid • cytochrome P450 • eicosanoid • ischemia/reperfusion • mitoKATP channel • MAPK
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