Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, 1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, Japan.
Atherosclerosis. 2010 Jun;210(2):430-7. doi: 10.1016/j.atherosclerosis.2009.12.031. Epub 2010 Jan 4.
Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.
尽管有人提出肾素-血管紧张素（RA）系统和组织蛋白酶参与了动脉粥样硬化斑块的形成和易损性，但 RA 系统和组织蛋白酶之间的相互作用尚不清楚。因此，我们研究了血管紧张素 II 型 1 型受体（AT1）拮抗剂奥美沙坦对载脂蛋白 E（apoE）缺陷小鼠接受高脂肪饮食时肱动脉粥样硬化斑块中组织蛋白酶水平和斑块稳定性的影响。在高脂肪饮食下，奥美沙坦（每天 3 毫克/千克）治疗可维持胶原和弹性蛋白的高水平，并减弱 apoE 缺陷小鼠动脉粥样硬化斑块的斑块形成和组织蛋白酶 S（Cat S）水平。奥美沙坦可抑制斑块中巨噬细胞的积聚。在巨噬细胞中观察到 Cat S 和 AT1 的免疫反应性。暴露于血管紧张素 II（Ang II）可增加培养的巨噬细胞中 Cat S mRNA 的量以及巨噬细胞介导的胶原酶和弹性蛋白酶活性，而奥美沙坦和 NADPH 氧化酶抑制剂 apocynin 可减弱这些作用。这些结果表明，源自巨噬细胞的 Cat S 参与了动脉粥样硬化斑块易损性的机制，AT1 阻滞剂除了抑制 Cat S 和巨噬细胞活性外，还能维持斑块稳定。
