Huang Menggui, Sannaningaiah Devaraja, Zhao Nan, Gong Yanqing, Grondolsky Jessica, Hoover-Plow Jane
Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
PLoS One. 2015 Feb 6;10(2):e0115284. doi: 10.1371/journal.pone.0115284. eCollection 2015.
Thrombosis, like other cardiovascular diseases, has a strong genetic component, with largely unknown determinants. EMILIN2, Elastin Microfibril Interface Located Protein2, was identified as a candidate gene for thrombosis in mouse and human quantitative trait loci studies. EMILIN2 is expressed during cardiovascular development, on cardiac stem cells, and in heart tissue in animal models of heart disease. In humans, the EMILIN2 gene is located on the short arm of Chromosome 18, and patients with partial and complete deletion of this chromosome region have cardiac malformations. To understand the basis for the thrombotic risk associated with EMILIN2, EMILIN2 deficient mice were generated. The findings of this study indicate that EMILIN2 influences platelet aggregation induced by adenosine diphosphate, collagen, and thrombin with both EMILIN2-deficient platelets and EMILIN2-deficient plasma contributing to the impaired aggregation response. Purified EMILIN2 added to platelets accelerated platelet aggregation and reduced clotting time when added to EMILIN2-deficient mouse and human plasma. Carotid occlusion time was 2-fold longer in mice with platelet-specific EMILIN2 deficiency, but stability of the clot was reduced in mice with both global EMILIN2 deficiency and with platelet-specific EMILIN2 deficiency. In vitro clot retraction was markedly decreased in EMILIN2 deficient mice, indicating that platelet outside-in signaling was dependent on EMILIN2. EMILIN1 deficient mice and EMILIN2:EMILIN1 double deficient mice had suppressed platelet aggregation and delayed clot retraction similar to EMILIN2 mice, but EMILIN2 and EMILIN1 had opposing affects on clot retraction, suggesting that EMILIN1 may attenuate the effects of EMILIN2 on platelet aggregation and thrombosis. In conclusion, these studies identify multiple influences of EMILIN2 in pathophysiology and suggest that its role as a prothrombotic risk factor may arise from its effects on platelet aggregation and platelet mediated clot retraction.
与其他心血管疾病一样，血栓形成具有很强的遗传因素，其决定因素很大程度上尚不清楚。弹性微原纤维界面定位蛋白2（EMILIN2）在小鼠和人类数量性状基因座研究中被确定为血栓形成的候选基因。在心血管发育过程中、心脏干细胞上以及心脏病动物模型的心脏组织中都有EMILIN2的表达。在人类中，EMILIN2基因位于18号染色体的短臂上，该染色体区域部分或完全缺失的患者会出现心脏畸形。为了了解与EMILIN2相关的血栓形成风险的基础，研究人员构建了EMILIN2基因缺陷小鼠。这项研究的结果表明，EMILIN2会影响由二磷酸腺苷、胶原蛋白和凝血酶诱导的血小板聚集，EMILIN2缺陷的血小板和EMILIN2缺陷的血浆都会导致聚集反应受损。将纯化的EMILIN2添加到血小板中可加速血小板聚集，添加到EMILIN2缺陷的小鼠和人类血浆中可缩短凝血时间。血小板特异性EMILIN2缺陷的小鼠颈动脉闭塞时间延长了2倍，但全身EMILIN2缺陷和血小板特异性EMILIN2缺陷的小鼠血栓稳定性均降低。EMILIN2缺陷小鼠的体外血块回缩明显减少，表明血小板外向内信号传导依赖于EMILIN2。EMILIN1缺陷小鼠和EMILIN2:EMILIN1双缺陷小鼠与EMILIN2缺陷小鼠一样，血小板聚集受到抑制，血块回缩延迟，但EMILIN2和EMILIN1对血块回缩有相反的影响，这表明EMILIN1可能会减弱EMILIN2对血小板聚集和血栓形成的影响。总之，这些研究确定了EMILIN2在病理生理学中的多种影响，并表明其作为促血栓形成风险因素的作用可能源于其对血小板聚集和血小板介导的血块回缩的影响。
