Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells.
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.
Hinkelmann
Urte
U
Department of Pharmacology and Toxicology, School of Pharmacy, Martin-Luther-University, 06099 Halle, Saale, Germany.
Grosser
Nina
N
Erdmann
Kati
K
Schröder
Henning
H
Immenschuh
Stephan
S
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D019821:Simvastatin; D006419:Heme Oxygenase (Decyclizing)