Haruna Yoshisuke, Morita Yoshitaka, Yada Toyotaka, Satoh Minoru, Fox David A, Kashihara Naoki
Kawasaki Medical School, Matsushima, Kurashiki, Japan.
Arthritis Rheum. 2007 Jun;56(6):1827-35. doi: 10.1002/art.22632.
To investigate the effect of statins on vascular dysfunction in rat adjuvant-induced arthritis (AIA).
Fluvastatin (5 mg/kg/day) was administered orally to rats with AIA, for 21 days after the onset of arthritis. The vasodilatory response to acetylcholine of aortic rings isolated from rats with AIA that were not treated or were treated with fluvastatin and from normal rats was determined. The amounts of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine in aortas were measured by Western blotting. In vitro and in situ superoxide production in aortas was evaluated based on fluorogenic oxidation of dihydroethidium to ethidium. Expression of NAD(P)H components and endothelial nitric oxide synthase (eNOS) in aortas was examined by real-time reverse transcriptase-polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin, a critical eNOS cofactor, were determined by high-performance liquid chromatography.
Fluvastatin reversed endothelial dysfunction in AIA without affecting the clinical severity of arthritis or serum cholesterol concentration. Fluvastatin reduced the amounts of HNE and nitrotyrosine in the aorta, and the levels of superoxide expressed in endothelial cells and smooth muscle cells in the tissue, in rats with AIA. NADH- or L-arginine-induced superoxide production was not observed in the aortic samples from fluvastatin-treated rats with AIA. Fluvastatin decreased the levels of expression of messenger RNA for p22phox, a NAD(P)H oxidase component, in the aortas of rats with AIA, but did not affect the expression of eNOS. Serum levels of tetrahydrobiopterin were significantly reduced in rats with AIA, and were increased by administration of fluvastatin.
Our findings demonstrate that fluvastatin has potent vascular protective effects in AIA and provide additional scientific rationale for the use of statins to reduce cardiovascular mortality in patients with rheumatoid arthritis.
研究他汀类药物对大鼠佐剂性关节炎（AIA）血管功能障碍的影响。
对患AIA的大鼠口服氟伐他汀（5毫克/千克/天），在关节炎发作后持续给药21天。测定未接受治疗、接受氟伐他汀治疗的患AIA大鼠以及正常大鼠分离的主动脉环对乙酰胆碱的血管舒张反应。通过蛋白质印迹法测量主动脉中4-羟基-2-壬烯醛（HNE）和硝基酪氨酸的含量。基于二氢乙锭向乙锭的荧光氧化评估主动脉的体外和原位超氧化物生成。通过实时逆转录聚合酶链反应和蛋白质印迹法检测主动脉中NAD（P）H成分和内皮型一氧化氮合酶（eNOS）的表达。通过高效液相色谱法测定关键eNOS辅因子四氢生物蝶呤的血清水平。
氟伐他汀可逆转AIA中的内皮功能障碍，而不影响关节炎的临床严重程度或血清胆固醇浓度。氟伐他汀降低了患AIA大鼠主动脉中HNE和硝基酪氨酸的含量，以及组织中内皮细胞和平滑肌细胞中超氧化物的水平。在接受氟伐他汀治疗且患AIA的大鼠的主动脉样本中未观察到NADH或L-精氨酸诱导的超氧化物生成。氟伐他汀降低了患AIA大鼠主动脉中NAD（P）H氧化酶成分p22phox的信使核糖核酸表达水平，但不影响eNOS的表达。患AIA大鼠的血清四氢生物蝶呤水平显著降低，而氟伐他汀给药后有所升高。
我们的研究结果表明，氟伐他汀在AIA中具有强大的血管保护作用，并为使用他汀类药物降低类风湿性关节炎患者心血管死亡率提供了额外的科学依据。
