Martínez-Miguel Patricia, Raoch Viviana, Zaragoza Carlos, Valdivielso Jose Manuel, Rodríguez-Puyol Manuel, Rodríguez-Puyol Diego, López-Ongil Susana
P. Martínez-Miguel and V. Raoch contributed equally to the manuscript; Research Unit and Nephrology Section, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid.
Centro Nacional de Investigaciones Cardiovascular (CNIC), Madrid, Lérida, Spain.
J Lipid Res. 2009 Mar;50(3):364-375. doi: 10.1194/jlr.M800215-JLR200. Epub 2008 Nov 7.
The aim of our study was to analyze the relationships between atherosclerosis and endothelin-converting enzyme-1 (ECE-1). Four-week-old C57BL/6J [wild-type (WT)] and apolipoprotein E-deficient (apoE) mice were fed with a standard or Western-type fat diet for 8 wks. ApoE showed atherosclerotic lesions in the aorta, higher blood pressure and vascular lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein content than WT. ApoE showed a significant increase in ECE-1 protein content and mRNA expression in aorta, lung, and kidney, without changes in heart. When an ECE-1 inhibitor, FR-901533, was administered to them, blood pressure decreased in apoE on fat diet versus apoE on normal diet and WT. ECE-1 and LOX-1 protein content were elevated in peripheral blood mononuclear cells (PBMC) from hypercholesterolemic patients. In order to study the mechanism involved in this ECE-1 up-regulation, bovine aortic endothelial cells (BAEC) were treated with oxidized-low density lipoproteins (oxLDL). OxLDL, but not LDL, increased ECE-1 protein content, mRNA expression and promoter activity. Our results demonstrate that ECE-1 increases in different atherosclerosis situations. Up-regulation of ECE-1 could contribute, at least partially, to the development of hypertension seen in apoE mice, because FR-901533 avoided it. Probably, atherosclerotic situations course with an increase of oxLDL, which is able to induce ECE-1 expression with the subsequent potential pathological effects.
我们研究的目的是分析动脉粥样硬化与内皮素转换酶-1（ECE-1）之间的关系。给4周龄的C57BL/6J[野生型（WT）]和载脂蛋白E缺陷（apoE）小鼠喂食标准或西式脂肪饮食8周。与WT相比，apoE小鼠的主动脉出现动脉粥样硬化病变、血压更高且血管凝集素样氧化低密度脂蛋白受体-1（LOX-1）蛋白含量更高。apoE小鼠主动脉、肺和肾脏中的ECE-1蛋白含量和mRNA表达显著增加，而心脏中无变化。当给它们施用ECE-1抑制剂FR-901533时，与正常饮食的apoE小鼠和WT相比，高脂饮食的apoE小鼠血压下降。高胆固醇血症患者外周血单核细胞（PBMC）中的ECE-1和LOX-1蛋白含量升高。为了研究这种ECE-1上调所涉及的机制，用氧化低密度脂蛋白（oxLDL）处理牛主动脉内皮细胞（BAEC）。oxLDL而非LDL增加了ECE-1蛋白含量、mRNA表达和启动子活性。我们的结果表明，在不同的动脉粥样硬化情况下ECE-1都会增加。ECE-1的上调可能至少部分促成了apoE小鼠中出现的高血压，因为FR-901533可避免这种情况。可能动脉粥样硬化情况下oxLDL增加，oxLDL能够诱导ECE-1表达并产生后续潜在的病理效应。
