Apolipoprotein(a) stimulates nuclear translocation of β-catenin: a novel pathogenic mechanism for lipoprotein(a).
Apolipoprotein(a) stimulates nuclear translocation of β-catenin: a novel pathogenic mechanism for lipoprotein(a).
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DOI：
10.1091/mbc.e12-08-0637
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发表时间：
2013-02
影响因子：
3.3
通讯作者：
Koschinsky ML
中科院分区：
文献类型：
--
作者：
Cho T;Romagnuolo R;Scipione C;Boffa MB;Koschinsky ML
载脂蛋白（a）（apo（a））是脂蛋白（a）的主要成分，通过引起内皮细胞功能障碍加速动脉粥样硬化。这项研究揭示了促动脉粥样硬化和促炎症apo（a）介导的信号通路，涉及PTEN/PI 3 K/Akt/GSK 3 β，导致β-连环蛋白核转位和考克斯-2上调。脂蛋白（a）（Lp（a））与心血管疾病风险相关。这可能归因于Lp（a）引起内皮功能障碍的能力。我们以前报道过载脂蛋白（a）（apo（a）; Lp（a）的独特的含Kringle组分）在血管内皮细胞中促进细胞骨架重排，导致细胞通透性增加。这些作用需要apo（a）中的强赖氨酸结合位点（LBS）。我们现在报道，载脂蛋白（a）诱导核β-连环蛋白介导的环氧合酶-2（考克斯-2）表达和前列腺素E2分泌，表明Lp（a）具有促炎作用。Apo（a）以Src依赖性方式引起VE-钙粘蛋白/β-连环蛋白复合物的破坏，降低β-连环蛋白磷酸化，增加Akt和糖原合成酶激酶-3 β的磷酸化，最终导致β-连环蛋白的核转位增加;所有这些作用都是apo（a）减弱10号染色体上缺失的磷酸酶和张力蛋白同源物活性的下游作用。使用缺乏强LBS的突变型apo（a），不存在apo（a）对考克斯-2表达的β-连环蛋白介导的作用。令人感兴趣的是，apo（a）的正常和LBS突变形式以类似的方式与人脐静脉内皮细胞结合，并且两者的结合都不受赖氨酸类似物的影响。综上所述，我们的发现提示了一种新的机制，apo（a）通过调节血管内皮细胞功能诱导促炎和促动脉粥样硬化作用。
Apolipoprotein(a) (apo(a)), the distinguishing component of lipoprotein(a), accelerates atherosclerosis by provoking endothelial cell dysfunction. This study unravels proatherosclerotic and proinflammatory apo(a)-mediated signaling pathways involving PTEN/PI3K/Akt/GSK3β that result in β-catenin nuclear translocation and up-regulation of COX-2. Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease risk. This may be attributable to the ability of Lp(a) to elicit endothelial dysfunction. We previously reported that apolipoprotein(a) (apo(a); the distinguishing kringle-containing component of Lp(a)) elicits cytoskeletal rearrangements in vascular endothelial cells, resulting in increased cellular permeability. These effects require a strong lysine-binding site (LBS) in apo(a). We now report that apo(a) induces both nuclear β-catenin–mediated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 secretion, indicating a proinflammatory role for Lp(a). Apo(a) caused the disruption of VE-cadherin/β-catenin complexes in a Src-dependent manner, decreased β-catenin phosphorylation, and increased phosphorylation of Akt and glycogen synthase kinase-3β, ultimately resulting in increased nuclear translocation of β-catenin; all of these effects are downstream of apo(a) attenuation of phosphatase and tensin homologue deleted on chromosome 10 activity. The β-catenin–mediated effects of apo(a) on COX-2 expression were absent using a mutant apo(a) lacking the strong LBS. Of interest, the normal and LBS mutant forms of apo(a) bound to human umbilical vein endothelial cells in a similar manner, and the binding of neither was affected by lysine analogues. Taken together, our findings suggest a novel mechanism by which apo(a) can induce proinflammatory and proatherosclerotic effects through modulation of vascular endothelial cell function.