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(Hypertension. 2000;36:923.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Fluvastatin Upregulates Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Vascular Smooth Muscle Cells

Hong Chen; Uichi Ikeda; Masahisa Shimpo; Michiyo Ikeda; Seiji Minota; Kazuyuki Shimada

From the Departments of Cardiology (H.C., U.I., M.S., K.S.) and Clinical Immunology (M.I., S.M.), Jichi Medical School, and the Health Science Center (M.I.), Utsunomiya University, Tochigi, Japan.

Correspondence to Uichi Ikeda, MD, PhD, Department of Cardiology, Jichi Medical School, Minamikawachi-Machi, Tochigi 329-0498, Japan. E-mail uikeda{at}jichi.ac.jp

Abstract—Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1ß (IL-1ß)–induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10^-8 to 10^-5 mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1ß induced nuclear factor-B activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1ß–induced nitrite accumulation in VSMCs. These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.

Key Words: nitric oxide • atherosclerosis • interleukins • muscle, smooth

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