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(Hypertension. 2001;38:1024.)
© 2001 American Heart Association, Inc.

Scientific Contributions

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Upregulate Inducible NO Synthase Expression and Activity in Vascular Smooth Muscle Cells

Alexey Y. Kolyada; Alexandre Fedtsov; Nicolaos E. Madias

From the Department of Medicine, Tufts University School of Medicine, and the Division of Nephrology and the Tupper Research Institute, New England Medical Center, Boston, Mass.

Correspondence to Nicolaos E. Madias, MD, Division of Nephrology, New England Medical Center, Box 172, 750 Washington St, Boston, MA 02111. E-mail nmadias{at}lifespan.org

Abstract—— Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 µmol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N^G-monomethyl-L-arginine (500 µmol/L). Activity of iNOS, determined by the conversion of L-arginine to L-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 µmol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 µmol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the -1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 µmol/L). Electromobility and supershift assays using a nuclear factor-B (NF-B) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-B reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-B pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-B. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis.

Key Words: nitric oxide synthase • transcription • cholesterol • atherosclerosis • lipids

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