Arishiro Kumiko, Hoshiga Masaaki, Negoro Nobuyuki, Jin Denan, Takai Shinji, Miyazaki Mizuo, Ishihara Tadashi, Hanafusa Toshiaki
First Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan.
J Am Coll Cardiol. 2007 Apr 3;49(13):1482-9. doi: 10.1016/j.jacc.2006.11.043. Epub 2007 Mar 21.
We sought to examine the effect of angiotensin receptor blocker (ARB) on the formation of lesions in the aortic valves of hypercholesterolemic rabbits.
Recently, atherosclerosis has been recognized as a mechanism that is responsible for calcific aortic stenosis. The effect of ARBs might help to prevent aortic stenosis because they have multiple antiatherosclerotic effects.
Male Japanese white rabbits (n = 36) were separated as follows: control with chow diet (C) and vehicle (V) groups, both of which were fed a 1% cholesterol diet for 8 weeks, and an ARB group (A), which was fed a 1% cholesterol diet for 8 weeks with ARB (olmesartan, 1 mg/kg/day) for the last 4 weeks.
This dose of olmesartan did not affect either blood pressure or cholesterol levels. Dietary cholesterol induced fatty deposition with macrophage accumulation and osteopontin coexpression in valve leaflets, whereas ARB decreased macrophage accumulation (% area: V, 9.3 +/- 0.34; A, 1.4 +/- 0.30; p = 0.003) and osteopontin expression (p = 0.017). Angiotensin-converting enzyme was also up-regulated in V and decreased by olmesartan (p = 0.015). Immunohistochemistry with anti-CD31 antibody revealed that dietary cholesterol disrupted and olmesartan preserved endothelial integrity on the lesion-prone aortic side of the valve (% CD31-positive circumference: V, 30 +/- 3.7; A, 62 +/- 4.8; p = 0.003). Numbers of alpha-smooth muscle actin-positive myofibroblasts were increased in V and decreased by olmesartan (p = 0.003). Real-time polymerase chain reaction revealed that increased amounts of messenger ribonucleic acid for osteoblast-specific transcription factor core binding factor alpha-1 in V were diminished by olmesartan.
Atherosclerotic changes in the aortic valves of rabbits fed with cholesterol were inhibited by ARB, whereas endo-thelial integrity was preserved and transdifferentiation into myofibroblasts and/or osteoblasts in valve leaflets was inhibited.
我们试图研究血管紧张素受体阻滞剂（ARB）对高胆固醇血症兔主动脉瓣病变形成的影响。
最近，动脉粥样硬化已被认为是导致钙化性主动脉瓣狭窄的一种机制。ARB的作用可能有助于预防主动脉瓣狭窄，因为它们具有多种抗动脉粥样硬化作用。
将36只雄性日本白兔分为以下几组：普通饮食对照组（C）和赋形剂对照组（V），两组均给予1%胆固醇饮食8周；ARB组（A），给予1%胆固醇饮食8周，在最后4周给予ARB（奥美沙坦，1毫克/千克/天）。
该剂量的奥美沙坦对血压和胆固醇水平均无影响。饮食中的胆固醇导致瓣膜小叶出现脂肪沉积、巨噬细胞积聚和骨桥蛋白共表达，而ARB减少了巨噬细胞积聚（面积百分比：V组，9.3±0.34；A组，1.4±0.30；p = 0.003）和骨桥蛋白表达（p = 0.017）。血管紧张素转换酶在V组中也上调，而奥美沙坦使其降低（p = 0.015）。用抗CD31抗体进行免疫组织化学分析显示，饮食中的胆固醇破坏了瓣膜易发生病变的主动脉侧的内皮完整性，而奥美沙坦则使其得以保留（CD31阳性周长百分比：V组，30±3.7；A组，62±4.8；p = 0.003）。α-平滑肌肌动蛋白阳性肌成纤维细胞的数量在V组中增加，而奥美沙坦使其减少（p = 0.003）。实时聚合酶链反应显示，V组中骨细胞特异性转录因子核心结合因子α-1的信使核糖核酸增加量被奥美沙坦减少。
ARB抑制了喂食胆固醇的兔主动脉瓣的动脉粥样硬化变化，同时保留了内皮完整性，并抑制了瓣膜小叶向肌成纤维细胞和/或成骨细胞的转分化。
