Murata Takahisa, Kinoshita Kazuya, Hori Masatoshi, Kuwahara Masayoshi, Tsubone Hirokazu, Karaki Hideaki, Ozaki Hiroshi
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2335-42. doi: 10.1161/01.ATV.0000186184.33537.48. Epub 2005 Sep 15.
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.
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.
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.
我们研究了氟伐他汀对缺氧诱导（1至3周，10%氧气）的肺动脉高压的影响，重点关注内皮型一氧化氮合酶（eNOS）活性。
口服氟伐他汀治疗（每日1mg/kg）可预防肺动脉高压的发生和进展，这通过右心室压力、右心室肥厚和肺动脉肌化来确定。我们还发现，氟伐他汀治疗可预防大鼠肺组织中缺氧诱导的cGMP生成减少，并恢复肺动脉的内皮依赖性舒张。我们发现这种有益作用不依赖于eNOS mRNA或蛋白表达的增加，而是依赖于对eNOS与小窝蛋白-1紧密偶联的抑制、eNOS与热休克蛋白90的解离以及缺氧诱导的eNOS Ser1177磷酸化的减少。此外，在全组织免疫染色中，氟伐他汀治疗可恢复缺氧诱导的肺内皮细胞中eNOS蛋白与小窝蛋白-1的凝聚。
这些结果表明，氟伐他汀通过在转录后水平保护eNOS活性，对慢性缺氧诱导的肺动脉高压发挥有益作用。
