Hayashi Toshio, Rani P Juliet Arockia, Fukatsu Akiko, Matsui-Hirai Hisako, Osawa Masako, Miyazaki Asaka, Tsunekawa Taku, Kano-Hayashi Hatsuyo, Iguchi Akihisa, Sumi Daigo, Ignarro Louis J
Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku Nagoya City 466-8550, Japan.
Atherosclerosis. 2004 Oct;176(2):255-63. doi: 10.1016/j.atherosclerosis.2003.12.034.
The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model.
We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits.
Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK.
Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂显著的抗动脉粥样硬化作用尚未在饮食诱导的兔重度高脂血症模型中得到证实。
我们研究了新型他汀类药物匹伐他汀对兔动脉粥样硬化的影响。
对去卵巢的雌性新西兰白兔喂食含0.3%胆固醇的饲料12周，分为服用匹伐他汀（0.1mg/kg/天）组（Gp.NK）和未服用组（Gp.HCD）。与Gp.HCD组相比，Gp.NK组血清胆固醇水平降低（772.8±70.2对1056.9±108.3mg/d），而甘油三酯和高密度脂蛋白胆固醇水平无显著变化。匹伐他汀治疗可改善乙酰胆碱和钙离子载体A23187刺激的一氧化氮依赖性反应以及N(G)-单甲基-L-精氨酸醋酸盐诱导的与张力相关的基础一氧化氮反应。匹伐他汀治疗可提高喂食胆固醇的兔主动脉中环磷酸鸟苷水平。在主动脉中，Gp.NK组动物内皮型一氧化氮合酶（eNOS）mRNA表达显著上调，超氧阴离子（O(2)(-)）生成略有减少。与Gp.HCD组相比，Gp.NK组兔主动脉弓和胸主动脉的动脉粥样硬化面积显著减小（Gp.NK组和Gp.HCD组主动脉弓和胸主动脉分别为15.1±5.3对41.9±10.2%，3.1±1.1对7.9±1.2%）。Gp.NK组抗巨噬细胞染色面积、基质金属蛋白酶1或2以及硝基酪氨酸阳性面积均减少。
匹伐他汀可延缓动脉粥样硬化形成的进程，并通过上调eNOS和减少O(2)(-)来改善一氧化氮的生物利用度。
