Electrophysiological properties of cardiomyocytes isolated from CYP2J2 transgenic mice.
CYP2J2 is abundant in cardiac tissue and active in the biosynthesis of eicosanoids such as epoxyeicosatrienoic acids (EETs). To determine the effects of CYP2J2 and its eicosanoid products in the heart, we characterized the electrophysiology of single cardiomyocytes isolated from adult transgenic (Tr) mice with cardiac-specific overexpression of CYP2J2. CYP2J2 Tr cardiomyocytes had a shortened action potential. At 90% repolarization, the action potential duration (APD) was 30.6 +/- 3.0 ms (n = 22) in wild-type (Wt) cells and 20.2 +/- 2.3 ms (n = 19) in CYP2J2 Tr cells (p < 0.005). This shortening was probably due to enhanced maximal peak transient outward K(+) currents (I(to,peak)), which were 38.6 +/- 2.8 and 54.4 +/- 4.9 pA/pF in Wt and CYP2J2 Tr cells, respectively (p < 0.05). In contrast, the late portion of the transient outward K(+) current (I(to,280ms)), the slowly inactivating outward K(+) current (I(K,slow)), and the voltage-gated Na(+) current (I(Na)) were not significantly altered in CYP2J2 Tr cells. N-Methylsulphonyl-6-(2-proparglyloxy-phenyl)hexanamide (MS-PPOH), a specific inhibitor of EET biosynthesis, significantly reduced I(to,peak) and increased APD in CYP2J2 Tr cardiomyocytes but not in Wt cells. Intracellular dialysis with a monoclonal antibody against CYP2J2 also significantly reduced I(to,peak) and increased APD in CYP2J2 Tr cardiomyocytes. Addition of 11,12-EET or 8-bromo-cAMP significantly reversed the MS-PPOH- or monoclonal antibody-induced changes in I(to,peak) and APD in CYP2J2 Tr cells. Together, our data demonstrate that shortening of the action potential in CYP2J2 Tr cardiomyocytes is associated with enhanced I(to,peak) via an EET-dependent, cAMP-mediated mechanism.
Ke
Qingen
Q
National Institutes of Health/NIEHS, 111 T. W. Alexander Drive, Building 101, Room D236, Research Triangle Park, NC 27709, USA. zeldin@niehs.nih.gov
Xiao
Yong-Fu
YF
Bradbury
J Alyce
JA
Graves
Joan P
JP
Degraff
Laura M
LM
Seubert
John M
JM
Zeldin
Darryl C
DC
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics / Q000502:physiology*; D011188:Potassium / Q000378:metabolism
D000577:Amides; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D015124:8-Bromo Cyclic Adenosine Monophosphate; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid; D011188:Potassium