Klouche M, May A E, Hemmes M, Messner M, Kanse S M, Preissner K T, Bhakdi S
Institute of Medical Microbiology, Johannes Gutenberg University of Mainz, Germany.
Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):784-93. doi: 10.1161/01.atv.19.3.784.
Circulating monocytes and T lymphocytes extravasate through the endothelium at sites of developing atheromatous lesions, where they tend to accumulate and mediate the progression of the disease. We have previously demonstrated the presence of an enzymatically degraded, nonoxidized form of LDL (E-LDL) in early human fatty streaks, which possesses major biological properties of an atherogenic lipoprotein. The effects of E-LDL on human endothelial cells have now been studied with respect to adhesion and transmigration of monocytes and T lymphocytes. E-LDL induced a rapid and dose-dependent selective adhesion of monocytes and T lymphocytes to endothelial cell monolayers within 30 minutes of incubation. Maximal increases in the number of adherent monocytes (8-fold) and of adherent T lymphocytes (4-fold) were observed after treatment with 50 microg/mL E-LDL. E-LDL was more active than oxidized LDL (ox-LDL), whereas native LDL produced only minor adhesive effects. Both E-LDL and ox-LDL enhanced transmigration of monocytes and of T lymphocytes through endothelial monolayers. Again, E-LDL was more potent than ox-LDL, inducing transmigration to a similar extent as N-formyl-Met-Leu-Phe. In endothelial cells, E-LDL stimulated upregulation of intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cells adhesion molecule-1 (PECAM-1), P-selectin, and E-selectin with distinct kinetics. Analyses with blocking antibodies indicated that ICAM-1 and P-selectin together mediated approximately 70% of cell adhesion, whereas blocking of PECAM-1 had no effect on adhesion but reduced transmigration to less than 50% of controls. E-LDL also upregulated expression of ICAM-1 in human aortic smooth muscle cells, and this correlated with increased adhesion of T lymphocytes. E-LDL is thus able to promote the selective adhesion of monocytes and T lymphocytes to the endothelium, stimulate transmigration of these cells, and foster their retention in the vessel wall by increasing their adherence to smooth muscle cells. These findings underline the potential significance of E-LDL in the pathogenesis of atherosclerosis.
循环中的单核细胞和T淋巴细胞在动脉粥样硬化病变形成部位穿过内皮细胞外渗，它们往往在这些部位聚集并介导疾病进展。我们之前已经证实在早期人类脂肪条纹中存在一种酶解的、非氧化形式的低密度脂蛋白（E-LDL），它具有致动脉粥样硬化脂蛋白的主要生物学特性。现在已经研究了E-LDL对人内皮细胞在单核细胞和T淋巴细胞黏附及迁移方面的影响。在孵育30分钟内，E-LDL诱导单核细胞和T淋巴细胞对内皮细胞单层的快速且剂量依赖性的选择性黏附。用50μg/mL E-LDL处理后，观察到黏附单核细胞数量（8倍）和黏附T淋巴细胞数量（4倍）的最大增加。E-LDL比氧化型低密度脂蛋白（ox-LDL）更具活性，而天然低密度脂蛋白仅产生轻微的黏附作用。E-LDL和ox-LDL都增强了单核细胞和T淋巴细胞穿过内皮细胞单层的迁移。同样，E-LDL比ox-LDL更有效，诱导迁移的程度与N-甲酰甲硫氨酰亮氨酰苯丙氨酸相似。在内皮细胞中，E-LDL以不同的动力学刺激细胞间黏附分子-1（ICAM-1）、血小板-内皮细胞黏附分子-1（PECAM-1）、P-选择素和E-选择素的上调。用阻断抗体分析表明，ICAM-1和P-选择素共同介导了约70%的细胞黏附，而阻断PECAM-1对黏附没有影响，但将迁移减少到对照组的不到50%。E-LDL还上调了人主动脉平滑肌细胞中ICAM-1的表达，这与T淋巴细胞黏附增加相关。因此，E-LDL能够促进单核细胞和T淋巴细胞对内皮的选择性黏附，刺激这些细胞的迁移，并通过增加它们对平滑肌细胞的黏附来促进它们在血管壁中的滞留。这些发现强调了E-LDL在动脉粥样硬化发病机制中的潜在重要性。
