Abstract
Cholesterol-independent, pleiotropic actions of HMG-CoA reductase inhibitors (statins) lead to anti-inflammatory and antioxidant actions by as yet unidentified mechanisms. This study explores the role of heme oxygenase-1 (HO-1) as target and potential mediator of rosuvastatin. In cultured human endothelial cells (ECV 304), rosuvastatin increased HO-1 mRNA and protein levels in a concentration-dependent fashion. HO-1 induction by rosuvastatin remained unaffected by mevalonate and N-nitro-l-arginine-methylester, showing that isoprenoid- and NO-dependent pathways were not involved. Pretreatment of endothelial cells with rosuvastatin reduced NADPH-dependent production of oxygen radicals. The HO-1 metabolite bilirubin, when added exogenously to the cells, virtually abolished NADPH-dependent oxidative stress. Rosuvastatin-induced inhibition of free radical formation was rescued in the presence of the HO inhibitor, tin protoporphyrin-IX. Our results demonstrate that HO-1 is a target site and antioxidant mediator of rosuvastatin in endothelial cells. This novel pathway may contribute to and partially explain the pleiotropic antiatherogenic actions of rosuvastatin.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 871-876 |
| Number of pages | 6 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 325 |
| Issue number | 3 |
| DOIs | |
| State | Published - Dec 17 2004 |
Keywords
- Antioxidant
- Bilirubin
- Cytoprotection
- Endothelial cells
- Free radicals
- Gene expression
- HMG-CoA reductase inhibitor
- Heme oxygenase
- Pleiotropic action
- Rosuvastatin