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(Circulation. 2004;110:856-861.)
© 2004 American Heart Association, Inc.

Original Articles

Antioxidant Effects of Statins via S-Nitrosylation and Activation of Thioredoxin in Endothelial Cells

A Novel Vasculoprotective Function of Statins

From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.

Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de

Received October 6, 2003; de novo received December 19, 2003; revision received April 8, 2004; accepted April 12, 2004.

Background— HMG-CoA reductase inhibitors (statins) are lipid-lowering drugs that also exert pleiotropic vasculoprotective effects via activation of the endothelial NO synthesis. NO induces S-nitrosylation of target proteins. S-Nitrosylation of the antioxidant enzyme thioredoxin was recently shown to enhance its activity, thereby reducing intracellular reactive oxygen species. Therefore, we investigated whether statins may exert an antioxidant activity in endothelial cells via S-nitrosylation of thioredoxin.

Methods and Results— Statins dose- and time-dependently increased the overall level of S-nitrosylated proteins in endothelial cells (atorvastatin 0.1 µmol/L, 206±30% increase; simvastatin 1 µmol/L, 214±19% increase; mevastatin 1 µmol/L, 191±10% increase). The increased S-nitrosylation was blocked by an NO-synthase inhibitor and mevalonate. Moreover, S-nitrosylation of thioredoxin was also significantly augmented after atorvastatin treatment. The atorvastatin-mediated increase in S-nitrosylation was associated with an enhanced enzymatic activity of thioredoxin (atorvastatin, 157±9% increase). This resulted in a significant reduction of intracellular reactive oxygen species within the endothelial cells. In contrast, in endothelial cells overexpressing a thioredoxin construct in which the S-nitrosylation acceptor amino acid cysteine 69 was replaced by serine [TRX(C69S)], atorvastatin did not activate the redox-regulatory activity of thioredoxin. Moreover, overexpression of the non-nitrosylatable thioredoxin TRX(C69S) abolished atorvastatin-mediated reduction of reactive oxygen species.

Conclusions— Here, we demonstrate a novel antioxidant mechanism by which statins reduce reactive oxygen species in endothelial cells. Statin-mediated S-nitrosylation of thioredoxin enhanced the enzymatic activity of thioredoxin, resulting in a significant reduction in intracellular reactive oxygen species.

Key Words: antioxidants • nitric oxide • endothelium

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