Shiraishi Yuji, Watanabe Takuya, Suguro Toshiaki, Nagashima Masaharu, Kato Rina, Hongo Shigeki, Itabe Hiroyuki, Miyazaki Akira, Hirano Tsutomu, Adachi Mitsuru
First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
J Hypertens. 2008 Oct;26(10):1955-65. doi: 10.1097/HJH.0b013e32830b61d8.
Our recent studies have indicated that urotensin II, the most potent vasoconstrictor peptide identified to date, potentiates human macrophage foam cell formation and vascular smooth muscle cell proliferation, and its levels are increased in the plasma of hypertensive patients with carotid atherosclerotic plaques. In the present study, we investigated the enhancing effect of urotensin II on atherosclerosis in apolipoprotein E-knockout mice and its suppression by 4-aminoquinoline, an urotensin II receptor-selective antagonist.
Urotensin II, urotensin II + 4-aminoquinoline, or vehicle was infused for 4 weeks through an osmotic mini-pump into 9-week-old apolipoprotein E-knockout mice on a high-fat diet. Aortic atherosclerosis and foam cell formation in exudate peritoneal macrophages were examined.
Atherosclerotic lesions as well as plasma levels of urotensin II, reactive oxygen species, and oxidized low-density lipoprotein and oxidized low-density lipoprotein-induced foam cell formation were significantly greater in urotensin II-infused mice than vehicle-infused controls. Western blotting analysis showed increased expression of scavenger receptors (CD36 and scavenger receptor class A) and acyl-CoA:cholesterol acyltransferase-1 in these macrophages. Increases in these parameters were significantly reduced by addition of 4-aminoquinoline. In apolipoprotein E-knockout mice even without urotensin II infusion, the treatment with 4-aminoquinoline for 8 weeks significantly prevented the development of atherosclerotic lesions.
Our results provide the first evidence that increased plasma urotensin II level stimulates oxidized low-density lipoprotein and reactive oxygen species production and macrophage foam cell formation via increased expression of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1, contributing to the development of atherosclerosis in apolipoprotein E-deficient mice. Urotensin II receptor antagonism may be a promising therapeutic strategy against atherosclerosis.
我们最近的研究表明，尾加压素II是迄今为止发现的最强效的血管收缩肽，可增强人巨噬细胞泡沫细胞形成和血管平滑肌细胞增殖，且在伴有颈动脉粥样硬化斑块的高血压患者血浆中其水平升高。在本研究中，我们调查了尾加压素II对载脂蛋白E基因敲除小鼠动脉粥样硬化的增强作用以及尾加压素II受体选择性拮抗剂4-氨基喹啉对其的抑制作用。
通过渗透微型泵将尾加压素II、尾加压素II + 4-氨基喹啉或赋形剂注入9周龄高脂饮食的载脂蛋白E基因敲除小鼠体内，持续4周。检测主动脉粥样硬化及渗出性腹腔巨噬细胞中泡沫细胞的形成情况。
与注入赋形剂的对照组相比，注入尾加压素II的小鼠动脉粥样硬化病变以及血浆尾加压素II、活性氧、氧化型低密度脂蛋白水平和氧化型低密度脂蛋白诱导的泡沫细胞形成均显著增加。蛋白质印迹分析显示这些巨噬细胞中清道夫受体（CD36和A类清道夫受体）和酰基辅酶A：胆固醇酰基转移酶-1的表达增加。添加4-氨基喹啉可显著降低这些参数的增加。在未注入尾加压素II的载脂蛋白E基因敲除小鼠中，用4-氨基喹啉治疗8周可显著预防动脉粥样硬化病变的发展。
我们的结果首次证明，血浆尾加压素II水平升高通过增加CD36、A类清道夫受体和酰基辅酶A：胆固醇酰基转移酶-1的表达，刺激氧化型低密度脂蛋白和活性氧生成以及巨噬细胞泡沫细胞形成，促进载脂蛋白E缺乏小鼠动脉粥样硬化的发展。尾加压素II受体拮抗作用可能是一种有前景的抗动脉粥样硬化治疗策略。
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