Sotiriou Sotirios N, Orlova Valeria V, Al-Fakhri Nadia, Ihanus Eveliina, Economopoulou Matina, Isermann Berend, Bdeir Khalil, Nawroth Peter P, Preissner Klaus T, Gahmberg Carl G, Koschinsky Marlys L, Chavakis Triantafyllos
Experimental Immunology Branch, NCI, NIH, Bethesda, Maryland 20892, USA.
FASEB J. 2006 Mar;20(3):559-61. doi: 10.1096/fj.05-4857fje. Epub 2006 Jan 10.
Lipoprotein(a) [Lp(a)], consisting of LDL and the unique constituent apolipoprotein(a) [apo(a)], which contains multiple repeats resembling plasminogen kringle 4, is considered a risk factor for the development of atherosclerotic disorders. However, the underlying mechanisms for the atherogenicity of Lp(a) are not completely understood. Here, we define a novel function of Lp(a) in promoting inflammatory cell recruitment that may contribute to its atherogenicity. Through its apo(a) moiety Lp(a) specifically interacts with the beta2-integrin Mac-1, thereby promoting the adhesion of monocytes and their transendothelial migration in a Mac-1-dependent manner. Interestingly, the interaction between Mac-1 and Lp(a) was strengthened in the presence of proatherogenic homocysteine and was blocked by plasminogen/angiostatin kringle 4. Through its interaction with Mac-1, Lp(a) induced activation of the proinflammatory transcription factor NFkappaB, as well as the NFkappaB-related expression of prothrombotic tissue factor. In atherosclerotic coronary arteries Lp(a) was found to be localized in close proximity to Mac-1 on infiltrating mononuclear cells. Taken together, our data demonstrate that Lp(a), via its apo(a) moiety, is a ligand for the beta2-integrin Mac-1, thereby facilitating inflammatory cell recruitment to atherosclerotic plaques. These observations suggest a novel mechanism for the atherogenic properties of Lp(a).
脂蛋白(a)[Lp(a)]由低密度脂蛋白(LDL)和独特成分载脂蛋白(a)[apo(a)]组成，apo(a)含有多个类似于纤溶酶原kringle 4的重复序列，被认为是动脉粥样硬化性疾病发生的危险因素。然而，Lp(a)致动脉粥样硬化的潜在机制尚未完全明确。在此，我们定义了Lp(a)在促进炎症细胞募集方面的一种新功能，这可能有助于其致动脉粥样硬化作用。通过其apo(a)部分，Lp(a)特异性地与β2整合素Mac-1相互作用，从而以Mac-1依赖的方式促进单核细胞的黏附及其跨内皮迁移。有趣的是，在促动脉粥样硬化的同型半胱氨酸存在的情况下，Mac-1与Lp(a)之间的相互作用增强，且被纤溶酶原/血管抑素kringle 4阻断。通过与Mac-1相互作用，Lp(a)诱导促炎转录因子NFκB的激活以及促血栓形成组织因子的NFκB相关表达。在动脉粥样硬化的冠状动脉中，发现Lp(a)定位于浸润的单核细胞上与Mac-1紧邻的位置。综上所述，我们的数据表明，Lp(a)通过其apo(a)部分，是β2整合素Mac-1的配体，从而促进炎症细胞募集到动脉粥样硬化斑块。这些观察结果提示了Lp(a)致动脉粥样硬化特性的一种新机制。
