Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1.
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.
Grosser
N
N
Department of Pharmacology and Toxiciology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale), Germany.
Erdmann
K
K
Hemmerle
A
A
Berndt
G
G
Hinkelmann
U
U
Smith
G
G
Schröder
H
H
D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005464:Fluorobenzenes / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006801:Humans; D008565:Membrane Proteins; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D005464:Fluorobenzenes; D008565:Membrane Proteins; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1