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Enhancement of Cardiac L-Type Ca²⁺ Currents in Transgenic Mice with Cardiac-Specific Overexpression of CYP2J2

The Charles A. Dana Research Institute and Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (Y.F.X., Q.K., J.P.M); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina (J.M.S., J.A.B., J.G., L.M.D., D.C.Z.); Department of Biochemistry, University of Texas Southwestern, Dallas, Texas (J.R.F.); and Division of Intramural Research, National Cancer Institute, NIH, Bethesda, Maryland (K.K., H.V.G.)

CYP2J2 is abundant in cardiomyocytes and is involved in the metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs), which affect multiple cell functions. In this study, we investigated the effect of overexpression of CYP2J2 on cardiac L-type Ca²⁺ currents (I_Ca) in adult transgenic mice. Cardiac-specific overexpression of CYP2J2 was achieved using the -myosin heavy chain promoter. I_Ca was recorded from isolated ventricular cardiomyocytes. Compared with the wild-type cardiomyocytes (n = 60), the density of I_Ca was significantly increased by 40 ± 9% in the CYP2J2 transgenic cardiomyocytes (n = 71; P < 0.001). N-Methylsulfonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH), a specific inhibitor of EET biosynthesis, and clotrimazole, a cytochrome P450 inhibitor, significantly reduced I_Ca in both wild-type and transgenic cardiomyocytes; however, MS-PPOH inhibited I_Ca to a greater extent in the CYP2J2 transgenic cells (n = 10) than in the wild-type cells (n = 10; P < 0.01). Addition of 11,12-EET significantly restored I_Ca in MS-PPOH-treated cells. Intracellular dialysis with either of two inhibitory monoclonal antibodies against CYP2J2 significantly reduced I_Ca in both wild-type and transgenic mice. Membrane-permeable 8-bromo-cAMP and the -adrenergic agonist isoproterenol significantly reversed the monoclonal antibody-induced inhibition of I_Ca. In addition, the total protein level of the 1 subunit of the Ca_v1.2 L-type Ca²⁺ channel was not altered in CYP2J2 transgenic hearts, but the phosphorylated portion was markedly increased. In conclusion, overexpression of CYP2J2 increases I_Ca in CYP2J2 transgenic cardiomyocytes via a mechanism that involves cAMP-protein kinase A-dependent phosphorylation of the L-type Ca²⁺ channel.

Address correspondence to: Dr. Yong-Fu Xiao, Medtronic Inc., 7000 Central Avenue NE, B252, Minneapolis, MN 55432-3576. E-mail: yongfu.xiao{at}medtronic.com

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