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1 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Cardiovascular Research Institute, Departments of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States
2 Cardiovascular Research Institute, Departments of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States
3 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
4 Departments of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States
5 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Cardiovascular Research Institute, Departments of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States; Department of Medicine (Cardiology), UMDNJ-New Jersey Medical School, Newark, New Jersey, United States
* To whom correspondence should be addressed. E-mail: ishikayo{at}umdnj.edu.
Although it has been shown that Epac1 mRNA is expressed ubiquitously and Epac2 mRNA predominantly in the brain and endocrine tissues, developmental and pathophysiological changes of these molecules have not been characterized. Developmental changes were analysed in murine heart, brain, kidneys and lungs by RT-PCR analysis, which revealed more drastic developmental changes of Epac2 mRNA than of Epac1. Only the Epac2 mRNA in kidney showed a transient expression pattern with dramatic decline into adulthood. In addition to developmental changes, we found that Epac gene expression was upregulated in myocardial hypertrophy induced by chronic isoproterenol infusion or pressure-overload by transverse aortic banding. Both Epac1 and Epac2 mRNA were upregulated in isoproterenol-induced left ventricular hypertrophy, whereas only Epac1 was increased in pressure-overload-induced hypertrophy. Stimulation of H9c2, cardiac myoblast cells, with fetal calf serum, which can induce myocyte hypertrophy, upregulated Epac1 protein expression. We also demonstrated that Epac was the limiting moiety, relative to Rap, in the Epac-Rap signaling pathway in terms of stoichiometry, and that Epac stimulation led to the activation of ERK1/2. Our data suggest the functional involvement of Epac in organogenesis and also in physiological as well as pathophysiological processes, such as cardiac hypertrophy. Furthermore our results suggest the importance of the stoichiometry of Epac over that of Rap in cellular biological effects.
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