Kumai Toshio, Oonuma Shigeko, Matsumoto Naoki, Takeba Yuko, Taniguchi Ryoko, Kamio Koji, Miyazu Osamu, Koitabashi Yu, Sekine Susumu, Tadokoro Mamoru, Kobayashi Shinichi
Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki 216-8511, Japan.
Life Sci. 2004 Mar 12;74(17):2129-42. doi: 10.1016/j.lfs.2003.09.051.
Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.
由于大鼠是抗动脉粥样硬化的物种，利用大鼠进行动脉粥样硬化的研究受到限制。本研究旨在建立大鼠动脉粥样硬化模型，研究一氧化氮（NO）失活和高脂血症的影响，并评估匹伐他汀（一种3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoA还原酶）抑制剂）对NO失活和高脂血症诱导的心血管系统变化的影响。使用4个月大的雄性自发性高血压高脂血症大鼠（SHHR）和Sprague-Dawley（SD）大鼠来研究1）用N(G)-硝基-L-精氨酸甲酯（L-NAME，100 mg/L）治疗对高脂饮食（HFD）处理的SHHR和SD大鼠的影响，以及2）匹伐他汀（Pit，0.3 mg/kg/天）对L-NAME和HFD处理的SHHR和SD大鼠主动脉变化的影响。给予L-NAME 1个月然后给予HFD 2个月，显著增加了SHHR中脂质的沉积和内皮厚度。L-NAME与HFD持续治疗在两种品系中均导致严重损伤并使内皮剥脱。L-NAME + HFD处理和L-NAME + HFD + Pit处理的SHHR的血浆总胆固醇显著高于对照SHHR。然而，L-NAME + HFD + Pit处理的SHHR主动脉中的脂质沉积相对较少。对照SHHR主动脉中的胆固醇浓度显著低于L-NAME + HFD处理的SHHR主动脉中的胆固醇浓度，而L-NAME + HFD + Pit处理的SHHR主动脉中的胆固醇浓度与对照SHHR主动脉中的胆固醇浓度相同。这些数据表明，Pit可阻止L-NAME + HFD处理的SHHR主动脉中的脂质沉积，而不改变血浆脂质谱。总之，NO失活和HFD诱导内皮脂质沉积，而HMG-CoA还原酶抑制剂可阻止SHHR中的脂质沉积。
