Hyperglycemia enhances VSMC proliferation with NF-kappaB activation by angiotensin II and E2F-1 augmentation by growth factors.
To clarify the mechanisms of hyperglycemia-induced proliferation of vascular smooth muscle cells (VSMC), we examined the effects of high glucose (HG) on nuclear factor (NF)-kappaB and E2F-1. Angiotensin II (Ang II) significantly enhanced DNA binding activity of NF-kappaB under HG (25.6 mM) conditions with an increase in p65 subunit of NF-kappaB, and did it slightly under normal glucose (NG; 5.6 mM) conditions. Ang II failed to induce E2F-1 expression, or its binding to the cdc2 promoter, even under HG conditions. HG greatly augmented the cdc2 inducibility of fetal calf serum (FCS), through the increase in E2F-1 activity. These data indicate that hyperglycemia contributes to abnormal proliferation of VSMC by two mechanisms; the induction of NF-kappaB activation by Ang II, which facilitates transcription of certain growth factors, and the augmentation of E2F-1 in response to growth factors.
Fujita
Nobuya
N
Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Kawachi-gun, 329-0498, Tochigi, Japan. fujitaem@jichi.ac.jp
Furukawa
Yusuke
Y
Du
Jian
J
Itabashi
Naoki
N
Fujisawa
Genro
G
Okada
Koji
K
Saito
Toshikazu
T
Ishibashi
Shun
S
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005312:Fetal Blood / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006943:Hyperglycemia / Q000473:pathology*; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D006133:Growth Substances; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000804:Angiotensin II; D004247:DNA; D016203:CDC2 Protein Kinase; D005947:Glucose