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Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells
Author(s) -
Chang Tuanjie,
Wang Rui,
Olson Douglas J.H.,
Mousseau Darrell D.,
Ross Andrew R.S.,
Wu Lingyun
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-178053
Subject(s) - vascular smooth muscle , akt1 , protein kinase b , phosphorylation , cell growth , methylglyoxal , chemistry , microbiology and biotechnology , kinase , biochemistry , biology , endocrinology , enzyme , smooth muscle
Methylglyoxal (MG), a reactive dicar‐bonyl molecule, can modify protein to form advanced glycation endproducts. Increased MG level has been implicated in proliferative vascular diseases, but the underlying mechanisms are not clear yet. The serine/ threonine kinase, Akt, regulates multiple signaling pathways that control cell proliferation. Using mass spectrometric analysis, we have detected the modification of Akt1 by MG at Cys 77 . This structural modification increased Akt1 phosphorylation at Ser 473 and Thr 308 . Akt1 phosphorylation and activity were also increased by MG treatment (<50 µM) in cultured vascular smooth muscle cells (VSMCs). MG treatment of VSMCs led to increased DNA synthesis (EC 50 =5.8 µM), cell proliferation, phosphorylation of p21 and glycogen synthase kinase‐3α/β (GSK‐3α/β), and increased cyclin‐dependent kinase 2 (CDK2) activity. These effects of MG were significantly inhibited by silencing Akt1 or by an Akt inhibitor. Overexpression of Akt1 Cys 77 Ser mutant in HEK‐293 cells increased cell proliferation and DNA synthesis, concurrent with an increase in Akt1 activity, which could not be further augmented by MG treatment. It is concluded that MG‐induced VSMC proliferation is mediated by the activation of Akt1 via the modification of Akt1 at Cys 77 .—Chang, T., Wang, R., Olson, D. J. H., Mousseau, D. D., Ross, A. R. S., Wu, L. Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells. FASEB J. 25, 1746–1757 (2011). www.fasebj.org