Expression of adhesion molecules by Lp(a): a potential novel mechanism for its atherogenicity
Expression of adhesion molecules by Lp(a): a potential novel mechanism for its atherogenicity
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DOI：
10.1096/fasebj.12.15.1765
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发表时间：
1998-12-01
期刊：
影响因子：
4.8
通讯作者：
Yacoub, M
中科院分区：
文献类型：
--
作者：
Allen, S;Khan, S;Yacoub, M
脂蛋白（a）是过早动脉粥样硬化的主要遗传危险因素。Lp（a）致动脉粥样硬化的机制尚未阐明，但可能涉及其干扰纤溶酶原活化的能力及其作为受体介导摄取后的脂蛋白颗粒的致动脉粥样硬化潜力。我们证明Lp（a）刺激血管细胞的产生。粘附分子1（VCAM-1）和E-选择素在培养的人冠状动脉内皮细胞（HCAEC）。这种作用是由于脂蛋白（a）引起细胞内游离钙升高所致，可被细胞内钙离子螯合剂BAPTA/AM所抑制。LDL和VLDL受体参与Lp（a）激活HCAEC被排除，因为LDL受体抗体（IgGC 7）或受体激活蛋白（一种与VLDL受体结合的配体拮抗剂）不能阻止Lp（a）诱导粘附分子。添加α 2-巨球蛋白以及肝素酶、软骨素酶、ABC和氯酸钠处理均未降低Lp（a）刺激的VCAM-1和E-选择素水平，表明低密度脂蛋白受体相关蛋白和细胞表面蛋白聚糖均不参与Lp（a）诱导的粘附分子产生。HCAEC上负责Lp（a）产生粘附分子的结合位点似乎也不涉及纤溶酶原受体，因为加入Glu-纤溶酶原、赖氨酸类似物E-氨基己酸或反式-4-氨基己酸并没有显著降低VCAM-1和E-选择素的水平。（氨甲基）-环己烷羧甲基酸（氨甲环酸），其通过与纤溶酶原中的kringle结构上携带的赖氨酸结合位点结合而起作用。相反，重组载脂蛋白（a）[r-apo（a）]与Lp（a）竞争，并减弱VCAM-1和E-选择素的表达。总之，我们已经鉴定了Lp（a）与HCAEC的钙依赖性相互作用，其能够诱导VCAM-1和E-选择素的有效表面表达，其似乎不涉及任何已知的潜在Lp（a）结合位点。由于白细胞向血管壁的募集似乎代表了动脉粥样硬化形成的重要早期事件之一，这种新描述的Lp（a）的内皮细胞激活作用将其置于致动脉粥样硬化疾病起始的关键时刻，并可能导致更好地理解Lp（a）在动脉粥样硬化血管生物学中的作用。
Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell. adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha(2)-macroglobulin as well as treatment with heparinase, chondroitinase,ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog E-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.