Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells

Urte Hinkelmann, Nina Grosser, Kati Erdmann, Henning Schröder, Stephan Immenschuh

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Heme oxygenase (HO)-1, which is the inducible isoform of the rate-limiting enzyme of heme degradation, has potent antioxidant and anti-inflammatory effects and is an emerging therapeutic target for the treatment of cardiovascular disease. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also termed statins, induce HO-1 gene expression in endothelial cells, but the underlying regulatory mechanisms are not well studied. To further investigate the statin-specific HO-1 regulation, we examined HO-1 gene expression by simvastatin in cell cultures of human endothelial cells. Simvastatin-dependent HO-1 gene activation was significantly reduced by pharmacological inhibition of the p38 MAPK and phosphotidylinositol-3-kinase (PI3K)/Akt pathways. Although HO-1 is considered to be primarily regulated at the transcriptional level, simvastatin induced activity of a human HO-1 promoter gene construct only to a minor extent. By contrast, studies with actinomycin D indicated that the half-life of HO-1 mRNA was significantly prolonged in the presence of simvastatin suggesting a post-transcriptional mode of HO-1 regulation. The increased HO-1 mRNA stability by this compound was blocked by inhibition of PI3K/Akt, but not by that of p38 MAPK. In conclusion, statin-dependent up-regulation of endothelial HO-1 is mainly regulated by stabilization of HO-1 mRNA via a PI3K/Akt-dependent signaling pathway.

Original languageEnglish (US)
Pages (from-to)118-124
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Volume41
Issue number1
DOIs
StatePublished - Sep 11 2010

Keywords

  • Endothelial cells
  • Gene regulation
  • Heme oxygenase-1
  • Signaling
  • Statins

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