Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK.
Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK.
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DOI：
10.1038/cddis.2016.235
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发表时间：
2017-01-12
影响因子：
9
通讯作者：
Ioannou Y
中科院分区：
文献类型：
--
作者：
Bourke LT;McDonnell T;McCormick J;Pericleous C;Ripoll VM;Giles I;Rahman A;Stephanou A;Ioannou Y
心肌梗死(MI)期间大量的心肌损伤发生在再灌注期，称为缺血/再灌注(I/R)损伤，占MI后心肌梗死组织总数的50%以上。在再灌流阶段，多种途径和机制的复杂相互作用被激活，最终导致细胞死亡，主要是通过细胞凋亡。狼疮小鼠模型有证据表明，狼疮免疫球蛋白，特别是抗磷脂(APL)抗体亚群，在肠系膜I/R损伤中是致病的。此外，已有研究表明，大多数循环致病性急性早幼粒细胞白血病的免疫优势表位位于β-2糖蛋白I(β2GPI)的N-末端结构域I(DI)。本研究描述了从狼疮和/或抗磷脂综合征患者中提取的纯化的免疫球蛋白在体外心肌细胞H/R模型中的增强致病作用。此外，我们还证明了含有APL的样本通过APL-β2GPI相互作用，导致促凋亡的p38MAPK通路激活，从而发挥致病作用。β2GPI结构域I的重组人多肽在液体相可抑制这一作用，提示该体外模型中的致病抗β2GPI抗体针对该结构域。
A significant amount of myocardial damage during a myocardial infarction (MI) occurs during the reperfusion stage, termed ischaemia/reperfusion (I/R) injury, and accounts for up to 50% of total infarcted tissue post-MI. During the reperfusion phase, a complex interplay of multiple pathways and mechanisms is activated, which ultimately leads to cell death, primarily through apoptosis. There is some evidence from a lupus mouse model that lupus IgG, specifically the antiphospholipid (aPL) antibody subset, is pathogenic in mesenteric I/R injury. Furthermore, it has previously been shown that the immunodominant epitope for the majority of circulating pathogenic aPLs resides in the N-terminal domain I (DI) of beta-2 glycoprotein I (β2GPI). This study describes the enhanced pathogenic effect of purified IgG derived from patients with lupus and/or the antiphospholipid syndrome in a cardiomyocyte H/R in vitro model. Furthermore, we have demonstrated a pathogenic role for aPL containing samples, mediated via aPL–β2GPI interactions, resulting in activation of the pro-apoptotic p38 MAPK pathway. This was shown to be inhibited using a recombinant human peptide of domain I of β2GPI in the fluid phase, suggesting that the pathogenic anti-β2GPI antibodies in this in vitro model target this domain.