on September 15, 2005
Published online before print September 15, 2005, doi: 10.1161/01.ATV.0000186184.33537.48
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Submitted on May 8, 2005
Accepted on July 28, 2005
Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension
Takahisa Murata *;
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.
* To whom correspondence should be addressed. 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.
Key words: endothelial nitric oxide synthase • fluvastatin • hypoxia
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