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First published on July 24, 2007; DOI: 10.1124/mol.107.035881

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Received for publication March 8, 2007.
Revised July 23, 2007.
Accepted for publication July 24, 2007.

Electrophysiological Properties of Cardiomyocytes Isolated from CYP2J2 Transgenic Mice

Qingen Ke 1, Yong-Fu Xiao 2, J. Alyce Bradbury 2, Joan Graves 2, Laura M. DeGraff 2, John Seubert 2, Darryl Zeldin 2*

1 Harvard Medical School 2 NIH/NIEHS

* Address correspondence to: E-mail: zeldin{at}niehs.nih.gov

Abstract

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 likely due to enhanced maximal peak transient outward K+ currents (Ito,peak) which were 38.6 ± 2.8 pA/pF in Wt cells and 54.4 ± 4.9 pA/pF in CYP2J2 Tr cells (p < 0.05). In contrast, the late portion of the transient outward K+ current (Ito,280ms), the slowly inactivating outward K+ current (IK,slow), and the voltage-gated Na+ current (INa) 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 Ito,peak and increased APD in CYP2J2 Tr cardiomyocytes, but not in Wt cells. Intracellular dialysis with a monoclonal antibody against CYP2J2 also significantly reduced Ito,peak and increased APD in CYP2J2 Tr cardiomyocytes. Addition of 11,12-EET or 8-Br-cAMP significantly reversed the MS-PPOH- or monoclonal antibody-induced changes in Ito,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 Ito,peak via an EET-dependent, cAMP-mediated mechanism.


Key words: Ion channel regulation, cAMP, Cytochrome P450


This article has been cited by other articles:


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 Am. J. Physiol. Heart Circ. Physiol.Home page
G. J. Gross, K. M. Gauthier, J. Moore, J. R. Falck, B. D. Hammock, W. B. Campbell, and K. Nithipatikom
Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2838 - H2844.
[Abstract] [Full Text] [PDF]


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