Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice
Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice
复制标题
DOI：
10.1161/01.res.0000174286.73200.d4
复制
发表时间：
2005-07-22
影响因子：
20.1
通讯作者：
Sawamura, T
中科院分区：
文献类型：
--
作者：
Inoue, K;Arai, Y;Sawamura, T
氧化低密度脂蛋白(OxLDL)诱导的内皮功能障碍与动脉粥样硬化和血管病变的发病机制密切相关。在实验性动脉粥样硬化动物模型和人类临床标本的动脉粥样硬化斑块中，内皮细胞OxLDL的受体--凝集素样氧化型低密度脂蛋白受体-1(LOX-1)的表达增加。在体外，LOX-1的激活改变了几个与内皮功能障碍有关的内皮细胞基因的表达。为了研究LOX-1在内皮功能障碍和由此导致的血管变化方面的作用，我们在C57BL/6和载脂蛋白E缺失小鼠(ApoEKO)背景下产生了LOX-1过度表达小鼠(LOXtg)。我们发现，转基因在冠状动脉和心肌细胞中的表达水平较高。LOXtg小鼠体内OxLDL摄取的增强与LOX-1的表达水平一致。在高脂状态下，LOXtg/apoEKO小鼠冠状动脉内均有OxLDL和8-羟基-2‘-脱氧鸟苷蓄积。LOXtg/apoEKO小鼠ICAM-1和VCAM-1的表达以及血管周围巨噬细胞的数量均显著高于对照组。两组动物的血流动力学曲线或血脂曲线均无差异。LOXtg/apoEKO小鼠表现出加速的心肌血管病变，高脂饮食3周后，LOXtg/apoEKO小鼠的动脉粥样斑样病变面积是非转基因小鼠的10倍。因此，LOX-1的过表达促进了高脂血症小鼠心肌内炎性血管病变的发生，这种作用可能是通过LOX-1过表达导致的内皮功能障碍来实现的。
Endothelial dysfunction induced by oxidized low-density lipoprotein ( OxLDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. Increased expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the receptor for OxLDL in endothelial cells, has been demonstrated in the atherosclerotic plaques from experimental atherosclerotic animal models and human clinical samples. In vitro, activation of LOX-1 alters the expression of several endothelial cell genes that are involved in endothelial dysfunction. To investigate the role of LOX-1 in terms of both endothelial dysfunction and resultant vascular changes, we generated mice overexpressing LOX-1 (LOXtg) in C57BL/6 and apolipoprotein E-null mice (apoEKO) backgrounds. We found that the expression of the transgene was prominent in coronary vessels and cardiomyocytes. The enhancement of OxLDL uptake in LOXtg mice was consistent with the expression level of LOX-1. Under hyperlipidemic conditions, both OxLDL and 8-hydroxy-2'-deoxyguanosine accumulated in the coronary arteries of LOXtg/apoEKO mice. The expression of ICAM-1 and VCAM-1, as well as the number of macrophages around blood vessels, were significantly increased in LOXtg/apoEKO mice compared with control littermates. There were no differences in either the hemodynamic profile or the plasma lipid profile between the 2 groups of animals. LOXtg/apoEKO mice displayed accelerated intramyocardial vasculopathy, and the atheroma-like lesion area was increased 10-fold in the LOXtg/apoEKO mice compared with nontransgenic littermates after 3-weeks on the high-fat diet. Thus, it is demonstrated that LOX-1 overexpression promotes inflammatory intramyocardial vasculopathy in a hyperlipidemic mouse model, and this effect is probably mediated through the endothelial dysfunction induced by overexpression of LOX-1.