Huang Menggui, Gong Yanqing, Grondolsky Jessica, Hoover-Plow Jane
Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
Department of Molecular Cardiology, the Cleveland Clinic Lerner Research Institute, Cleveland, Ohio; Department of Cardiovascular Medicine, the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland, Ohio.
Am J Pathol. 2014 May;184(5):1503-17. doi: 10.1016/j.ajpath.2014.01.010. Epub 2014 Mar 17.
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular diseases, but the mechanism is unclear. The pathogenic risk of Lp(a) is associated with elevated plasma concentration, small isoforms of apolipoprotein [apo(a)], the unique apolipoprotein of Lp(a), and a mimic of plasminogen. Inflammation is associated with both the initiation and recovery of cardiovascular diseases, and plasminogen plays an important role in leukocyte recruitment. Because Lp(a)/apo(a) is expressed only in primates, transgenic mice were generated, apo(a)tg and Lp(a)tg mice, to determine whether Lp(a)/apo(a) modifies plasminogen-dependent leukocyte recruitment or whether apo(a) has an independent role in vivo. Plasminogen activation was markedly reduced in apo(a)tg and Lp(a)tg mice in both peritonitis and vascular injury inflammatory models, and was sufficient to reduce matrix metalloproteinase-9 activation and macrophage recruitment. Furthermore, neutrophil recruitment and the neutrophil cytokines, CXCL1/CXCL2, were suppressed in apo(a)tg mice in the abdominal aortic aneurysm model. Reconstitution of CXCL1 or CXCL2 restored neutrophil recruitment in apo(a)tg mice. Apo(a) in the plasminogen-deficient background and Lp(a)tg mice were resistant to inhibition of macrophage recruitment that was associated with an increased accumulation of apo(a) in the intimal layer of the vessel wall. These data indicate that, in inflammation, Lp(a)/apo(a) suppresses neutrophil recruitment by plasminogen-independent cytokine inhibition, and Lp(a)/apo(a) inhibits plasminogen activation and regulates matrix metalloproteinase-9 activation and macrophage recruitment.
脂蛋白(a)[Lp(a)]是心血管疾病的独立危险因素，但其机制尚不清楚。Lp(a)的致病风险与血浆浓度升高、载脂蛋白[apo(a)]的小异构体（Lp(a)独特的载脂蛋白）以及纤溶酶原模拟物有关。炎症与心血管疾病的发生和恢复均相关，且纤溶酶原在白细胞募集中起重要作用。由于Lp(a)/apo(a)仅在灵长类动物中表达，因此构建了转基因小鼠，即apo(a)转基因小鼠和Lp(a)转基因小鼠，以确定Lp(a)/apo(a)是否会改变纤溶酶原依赖性白细胞募集，或者apo(a)在体内是否具有独立作用。在腹膜炎和血管损伤炎症模型中，apo(a)转基因小鼠和Lp(a)转基因小鼠的纤溶酶原激活均显著降低，且足以减少基质金属蛋白酶-9的激活和巨噬细胞募集。此外，在腹主动脉瘤模型中，apo(a)转基因小鼠的中性粒细胞募集以及中性粒细胞细胞因子CXCL1/CXCL2均受到抑制。补充CXCL1或CXCL2可恢复apo(a)转基因小鼠的中性粒细胞募集。在纤溶酶原缺陷背景下的apo(a)和Lp(a)转基因小鼠对巨噬细胞募集抑制具有抗性，这与apo(a)在血管壁内膜层的积累增加有关。这些数据表明，在炎症过程中，Lp(a)/apo(a)通过非纤溶酶原依赖性细胞因子抑制作用抑制中性粒细胞募集，且Lp(a)/apo(a)抑制纤溶酶原激活并调节基质金属蛋白酶-9的激活和巨噬细胞募集。
