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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2335.)
© 2005 American Heart Association, Inc.

Vascular Biology

Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension

Takahisa Murata; Kazuya Kinoshita; Masatoshi Hori; Masayoshi Kuwahara; Hirokazu Tsubone; Hideaki Karaki; Hiroshi Ozaki

From the Departments of Veterinary Pharmacology (T.M., K.K., M.H., H.K., H.O.) and Comparative Pathophysiology (M.K., H.T.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.

Correspondence to Takahisa Murata, DVM, PhD, Department of Veterinary Pharmacology, Graduate School of Agriculture, and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail murata{at}mail.vm.a.u-tokyo.ac.jp

Objective— We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O₂) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity.

Methods and Results— Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser¹¹⁷⁷–phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment.

Conclusion— These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.

We investigated the effect of fluvastatin on endothelial impairment in pulmonary hypertension and revealed that fluvastatin can restore the decrease in endothelial NO production through its protective effects against eNOS-tight coupling with caveolin-1 caused by chronic hypoxia.

Key Words: endothelial nitric oxide synthase • fluvastatin • hypoxia

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