Enhanced Postischemic Functional Recovery in CYP2J2 Transgenic Hearts Involves Mitochondrial ATP-Sensitive K+ Channels and p42/p44 MAPK Pathway

• Published in: Circulation research 2004-09, Vol.95 (5), p.506-514
• Main Authors: Seubert, John, Yang, Baichun, Bradbury, J Alyce, Graves, Joan, Degraff, Laura M., Gabel, Scott, Gooch, Rebecca, Foley, Julie, Newman, John, Mao, Lan, Rockman, Howard A., Hammock, Bruce D., Murphy, Elizabeth, Zeldin, Darryl C.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - physiology; Fatty Acids - metabolism; Flavoproteins - chemistry; Fluorescence; Fundamental and applied biological sciences. Psychology; Heart - anatomy & histology; Heart - physiopathology; Humans; In Vitro Techniques; MAP Kinase Signaling System; Membrane Proteins - physiology; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3 - physiology; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocardium - enzymology; Oxygenases - genetics; Oxygenases - physiology; Potassium Channel Blockers - pharmacology; Potassium Channels - physiology; Ventricular Function, Left; Ventricular Pressure - drug effects; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000139436.89654.c8

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.