Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages
Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages
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DOI：
10.1161/01.hyp.0000184226.99196.b5
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发表时间：
2005-10-01
期刊：
影响因子：
8.3
通讯作者：
Miyazaki, A
中科院分区：
文献类型：
--
作者：
Watanabe, T;Suguro, T;Miyazaki, A
人尾加压素If（U-II）是迄今为止发现的最强的血管收缩肽，其受体（UT）参与高血压和动脉粥样硬化。酰基辅酶A：胆固醇酰基转移酶-1（ACAT-1）将细胞内游离胆固醇转化为胆固醇酯（CE）储存在脂滴中，并在动脉粥样硬化病变中巨噬细胞源性泡沫细胞的形成中起重要作用。我们研究了U-II对人单核细胞衍生的巨噬细胞中ACAT-I表达和CE积累的影响。在单核细胞原代培养7天后，U-II以浓度依赖性方式增加ACAT活性。免疫印迹分析表明，25 nmol/L的U-II使ACAT-Ⅰ蛋白表达水平增加2.5倍，而抗U-II抗体、选择性UT受体拮抗剂可完全抑制U-II的作用（铀酰肽和4-氨基喹啉），一种G蛋白灭活剂（GDP-β-S）、c-Src蛋白酪氨酸激酶抑制剂（PP 2）、蛋白激酶C（PKC）抑制剂（rottlerin）、促分裂原活化蛋白激酶激酶（MEK）抑制剂（PD 98059）或Rho激酶（ROCK）抑制剂（Y27632）。北方印迹分析表明，在4种ACAT-Ⅰ mRNA转录本（2.8-、3.6-、4.3-和7.0-kb）中，2.8-和3.6-kb转录本水平被U-II（25 nmol/L）选择性上调约1.7倍。此外，U-II（25 nmol/L）显着增加乙酰化LDL（乙酰-LDL）诱导的CE在单核细胞衍生的巨噬细胞的积累，但不是清道夫受体A类（SR-A）的功能，评估[I-125]乙酰-LDL的内吞摄取。我们的研究结果表明，U-II可能通过上调ACAT-I表达通过UT受体/G-蛋白/c-Src/PKC/MEK和ROCK途径，而不是SR-A，从而在巨噬细胞源性泡沫细胞的形成中发挥新的作用，从而有助于动脉粥样硬化在高血压中的相对快速的发展。
Human urotensin If (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. We examined the effects of U-II on ACAT-I expression and CE accumulation in human monocyte-derived macrophages. U-II increased ACAT activity in a concentration-dependent manner after 7 days in monocyte primary culture. Immunoblotting analysis showed that U-II at 25 nmol/L increased ACAT-I protein expression level by 2.5-fold, which was completely abolished by anti-U-II antibody, selective UT receptor antagonists (urantide and 4-aminoquinoline), a G-protein inactivator (GDP-beta-S), a c-Src protein tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), a mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059), or a Rho kinase (ROCK) inhibitor (Y27632). Northern blotting analysis indicated that among the 4 ACAT-I mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the 2.8- and 3.6-kb transcript levels were selectively upregulated by approximate to 1.7-fold by U-II (25 nmol/L). Further, U-II (25 nmol/L) significantly increased acetylated LDL (acetyl-LDL)-induced CE accumulation in monocyte-derived macrophages but not scavenger receptor class A (SR-A) function as assessed by endocytic uptake of [I-125]acetyl-LDL. Our results suggest that U-II may play a novel role in the formation of macrophage-derived foam cells by upregulating ACAT-I expression via the UT receptor/G-protein/c-Src/PKC/MEK and ROCK pathways but not by SR-A, thus contributing to the relatively rapid development of atherosclerosis in hypertension.