Statins modulate transcriptional activity of heme-oxygenase-1 promoter in NIH 3T3 Cells

Mrad, May F., Mouawad, Charbel A., Al-Hariri, Moustafa, Eid, Assaad A., Alam, Jawed and Habib, Aida (2012) Statins modulate transcriptional activity of heme-oxygenase-1 promoter in NIH 3T3 Cells. Journal of Cellular Biochemistry, 113 11: 3466-3475. doi:10.1002/jcb.24223

Author Mrad, May F.
Mouawad, Charbel A.
Al-Hariri, Moustafa
Eid, Assaad A.
Alam, Jawed
Habib, Aida
Title Statins modulate transcriptional activity of heme-oxygenase-1 promoter in NIH 3T3 Cells
Journal name Journal of Cellular Biochemistry   Check publisher's open access policy
ISSN 0730-2312
Publication date 2012-11-01
Sub-type Article (original research)
DOI 10.1002/jcb.24223
Open Access Status Not Open Access
Volume 113
Issue 11
Start page 3466
End page 3475
Total pages 10
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract Statins, inhibitors of HMG CoA reductase, have pleiotropic effects independent of their capacity to lower cholesterol. Heme-oxygenase-1(HO-1) plays an important role as an anti-oxidant and anti-inflammatory enzyme. In the present study, we used NIH 3T3 cells which express HO-1 to investigate the molecular mechanisms of HO-1 induction by statins. Simvastatin or fluvastatin induced a significant increase in HO-1 protein expression and mRNA levels. Both statins stimulated activity of a mouse HO-1 promoter (-1,287 to +73 bp)/luciferase reporter gene, 3.25 ± 0.23 (Mean ± S.E.M., n = 15, P < 0.001, t-test) and 3.13 ± 0.33 (Mean ± S.E.M., n = 6, P < 0.001, t-test), respectively. This effect was more pronounced in the short proximal promoter than the full promoter of HO-1. Gel retardation experiments for C/EBP and upstream stimulatory factor (USF) DNA-binding activities using simvastatin- or fluvastatin-treated cells showed significant nuclear protein-DNA complexes which were supershifted with antibodies specific for C/EBP β and Î or USF-1 and USF-2. Point mutations of the proximal HO-1 promoter (-149 to +73 bp) for the myc/max which binds USF or the C/EBP binding sequences showed a reduction in statin-induced reporter activity whereas no role of the distal C/EBP binding elements located at -4 kb was observed. Moreover, overexpression of mutated C/EBP β and USF factor or the siRNA for both factors supported a role of these transcription factors in statin-dependent induction of HO-1, with a clearer effect for C/EBP.
Keyword Statins
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 18 September 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
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