14-3-3 inhibits insulin-like growth factor-I-induced proliferation of cardiac fibroblasts via a phosphatidylinositol 3-kinase-dependent pathway.
1. Insulin-like growth factor (IGF)-I plays an important role in the pathogenesis of heart disease and has been shown to strongly induce the proliferation of cardiac fibroblasts (CFs). It remains unknown whether 14-3-3 proteins, which are associated the regulation of signal transduction, affect IGF-I-induced CF proliferation. 2. In the present study, we investigated the effects of 14-3-3 proteins on CF proliferation in response to IGF-I. Proliferation of CFs was determined by cell counting and a bromodeoxyuridine incorporation assay. Phosphorylation of signalling molecules was evaluated by western blottling. Activity of nuclear factor of activated T cells (NFAT) was examined using a dual luciferase reporter gene assay and immunofluorescence. 3. It was found that adenovirus-mediated transfection of YFP-R18 peptide (AdR18), a known inhibitor of 14-3-3, significantly enhanced IGF-I-induced CF proliferation. This potentiation arose from an increase in phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and AKT (protein kinase B), inactivation of glycogen synthesis kinase (GSK) 3beta and increased NFAT activity. 4. Collectively, the results of the present study suggest that 14-3-3 proteins inhibit IGF-I-induced CF proliferation via a PI3-K-dependent NFAT signalling pathway. This finding may contribute to our understanding of the function of 14-3-3 proteins in the heart.
Qi
Jian-Yong
JY
Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
Xu
Ming
M
Lu
Zhi-Zhen
ZZ
Zhang
You-Yi
YY
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D048948:14-3-3 Proteins; D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase