Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice
Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice
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DOI：
10.1097/hjh.0b013e32830b61d8
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发表时间：
2008-10-01
影响因子：
4.9
通讯作者：
Adachi, Mitsuru
中科院分区：
文献类型：
--
作者：
Shiraishi, Yuji;Watanabe, Takuya;Adachi, Mitsuru
目的尾加压素II（urotensin II）是迄今发现的最强的缩血管肽，它能促进人巨噬细胞泡沫细胞的形成和血管平滑肌细胞的增殖，并在高血压合并颈动脉粥样硬化斑块患者血浆中升高。在本研究中，我们研究了尾加压素II对载脂蛋白E基因敲除小鼠动脉粥样硬化的增强作用及其抑制4-氨基喹啉，尾加压素II受体选择性拮抗剂。方法尾加压素II，尾加压素II + 4-氨基喹啉，或车辆4周通过渗透微型泵注入9周龄载脂蛋白E基因敲除小鼠高脂饮食。主动脉粥样硬化和渗出液腹腔巨噬细胞中的泡沫细胞形成examined.Results动脉粥样硬化病变以及尾加压素II，活性氧，氧化低密度脂蛋白和氧化低密度脂蛋白诱导的泡沫细胞形成的血浆水平显着大于尾加压素II输注的小鼠比溶媒输注的对照组。蛋白质印迹分析表明，清道夫受体（CD 36和清道夫受体A类）和酰基辅酶A：胆固醇酰基转移酶-1在这些巨噬细胞的表达增加。通过添加4-氨基喹啉，这些参数的增加显著降低。在载脂蛋白E基因敲除小鼠中，即使没有尾加压素II输注，用4-氨基喹啉治疗8周也显著防止了动脉粥样硬化病变的发展。结论我们的结果提供了第一个证据，即血浆尾加压素II水平升高通过增加CD 36、清道夫受体A类、和酰基辅酶A：胆固醇酰基转移酶-1，有助于载脂蛋白E缺陷小鼠动脉粥样硬化的发展。尾加压素II受体拮抗剂可能是一个有前途的治疗策略，对动脉粥样硬化。
Objective 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.Methods 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.Results 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.Conclusion 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.