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 probably due to enhanced maximal peak transient outward K+ currents (Ito,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 (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-bromo-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.
Footnotes
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This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.035881.
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ABBREVIATIONS: AA, arachidonic acid; EET, cis-epoxyeicosatrienoic acid; DHET, vic-dihydroxyeicosatrienoic acid; αMHC, α-myosin heavy chain; Tr, transgenic; Wt, wild type; MS-PPOH, N-methylsulfonyl-6-(2-proparglyloxyphenyl)hexanamide; MAb, monoclonal antibody against; 8-Br-cAMP, 8-bromo-cAMP; APD, action potential duration; PKA, protein kinase A; Ito,peak, maximal peak transient outward K+ current; Ito,280ms, late portion of the transient outward K+ current; INa, voltage-gated Na+ current; KATP, ATP-sensitive K+ channel; NS, not significant.
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↵1 Current affiliation: Cardiac Rhythm Disease Management, Medtronic Inc., Minneapolis, Minnesota.
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↵2 Current affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
- Received March 7, 2007.
- Accepted July 24, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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