期刊
MOLECULAR PHARMACOLOGY
卷 66, 期 6, 页码 1607-1616出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.104.004150
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资金
- NIGMS NIH HHS [GM31278] Funding Source: Medline
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 alpha-myosin heavy chain promoter. I-Ca was recorded from isolated ventricular cardiomyocytes. Compared with the wildtype 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 beta-adrenergic agonist isoproterenol significantly reversed the monoclonal antibody-induced inhibition of I-Ca. In addition, the total protein level of the alpha1 subunit of the Ca-v 1.2 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.
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