Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy.
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 analyzed in murine heart, brain, kidneys, and lungs by RT-PCR analysis, which revealed more drastic developmental changes of Epac2 mRNA than 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.
Ulucan
Coskun
C
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Wang
Xu
X
Baljinnyam
Erdene
E
Bai
Yunzhe
Y
Okumura
Satoshi
S
Sato
Motohiko
M
Minamisawa
Susumu
S
Hirotani
Shinichi
S
Ishikawa
Yoshihiro
Y
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002316:Cardiotonic Agents; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D006801:Humans; D006984:Hypertrophy; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D002316:Cardiotonic Agents; D002352:Carrier Proteins; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007527:Isoenzymes; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D012333:RNA, Messenger; C486707:Rapgef4 protein, mouse; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases; C463959:protein kinase A Calpha; D019205:GTP-Binding Protein alpha Subunits, Gs; D020827:rap1 GTP-Binding Proteins; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V; D007545:Isoproterenol