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 micromol/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.