Takami S, Yamashita S, Kihara S, Ishigami M, Takemura K, Kume N, Kita T, Matsuzawa Y
Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan.
Circulation. 1998 Mar 3;97(8):721-8. doi: 10.1161/01.cir.97.8.721.
We reported an increase in serum lipoprotein(a) [Lp(a)] levels in patients with thromboangiitis obliterans, suggesting that Lp(a) could also contribute to the pathogenesis of cardiovascular diseases by a mechanism different from atherosclerosis. Adhesion molecules were shown to contribute to the development of not only atherosclerotic but also inflammatory vascular diseases.
We evaluated the effect of Lp(a) on the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in human umbilical vein endothelial cells by a cell ELISA. Lp(a) dramatically enhanced the levels of ICAM-1 in a dose-dependent manner. A discernible increase in ICAM-1 expression was observed at a physiological concentration of 0.26 mmol cholesterol/L Lp(a) after 48-hour incubation. A 1.8-fold increase in ICAM-1 expression was observed 48 hours after the addition of Lp(a) (1.04 mmol cholesterol/L). Northern blot analysis demonstrated that the amount of ICAM-1 mRNA was increased after treatment with Lp(a). In contrast to ICAM-1, the expression of VCAM-1 and E-selectin was not significantly affected by Lp(a). Lp(a-) [apolipoprotein(a)- removed Lp(a) by reduction with dithiothreitol] and LDL had no significant effect on the expression of ICAM-1. In contrast, recombinant apolipoprotein(a) protein alone significantly enhanced ICAM-1 expression. Lp(a) decreased the level of active transforming growth factor (TGF)-beta in the conditioned medium. Furthermore, recombinant TGF-beta significantly decreased the Lp(a)-induced ICAM-1 expression. These findings suggested that Lp(a) may enhance the ICAM-1 expression by decreasing active TGF-beta level.
Lp(a) could contribute to the development of cardiovascular diseases by enhancing the expression of ICAM-1 in endothelial cells.
我们报道过血栓闭塞性脉管炎患者血清脂蛋白(a)[Lp(a)]水平升高，提示Lp(a)也可能通过一种不同于动脉粥样硬化的机制促成心血管疾病的发病过程。粘附分子不仅在动脉粥样硬化性血管疾病的发生发展中起作用，在炎症性血管疾病中也发挥作用。
我们通过细胞酶联免疫吸附测定法评估了Lp(a)对人脐静脉内皮细胞中细胞间粘附分子(ICAM)-1、血管细胞粘附分子(VCAM)-1和E-选择素表达的影响。Lp(a)以剂量依赖的方式显著提高了ICAM-1的水平。在生理浓度0.26 mmol胆固醇/L的Lp(a)孵育48小时后，可观察到ICAM-1表达有明显增加。加入Lp(a)(1.04 mmol胆固醇/L)48小时后，ICAM-1表达增加了1.8倍。Northern印迹分析表明，用Lp(a)处理后ICAM-1 mRNA的量增加。与ICAM-1不同，VCAM-1和E-选择素的表达未受到Lp(a)的显著影响。Lp(a-) [通过用二硫苏糖醇还原去除载脂蛋白(a)的Lp(a)]和低密度脂蛋白(LDL)对ICAM-1的表达没有显著影响。相反，单独的重组载脂蛋白(a)蛋白显著增强了ICAM-1的表达。Lp(a)降低了条件培养基中活性转化生长因子(TGF)-β的水平。此外，重组TGF-β显著降低了Lp(a)诱导的ICAM-1表达。这些发现提示Lp(a)可能通过降低活性TGF-β水平来增强ICAM-1的表达。
Lp(a)可通过增强内皮细胞中ICAM-1的表达促成心血管疾病的发生发展。
