SREBP inhibits VEGF expression in human smooth muscle cells.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs.
Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
Koka
K
Motoyama
Shinya
S
Fukumoto
Hidenori
H
Koyama
Masanori
M
Emoto
Hitoshi
H
Shimano
Koji
K
Maemura
Yoshiki
Y
Nishizawa
D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014469:Umbilical Arteries / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D006538:Heptanoic Acids; D011758:Pyrroles; D051780:Sterol Regulatory Element Binding Protein 1; D042461:Vascular Endothelial Growth Factor A; D000069059:Atorvastatin