Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation.
Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation.
复制标题
DOI：
10.1161/circulationaha.115.016540
复制
发表时间：
2015-12-08
期刊：
影响因子：
37.8
通讯作者：
Chauhan AK
中科院分区：
文献类型：
--
作者：
Dhanesha N;Ahmad A;Prakash P;Doddapattar P;Lentz SR;Chauhan AK
含有额外结构域A （Fn-EDA）的纤连蛋白剪接变体在健康人血浆中的含量可忽略不计，但在患有糖尿病和高胆固醇血症等合并症的患者中显著升高，这些合并症是中风的危险因素。然而，在这种情况下，Fn-EDA是否会使中风结果恶化，目前尚不清楚。我们在高胆固醇血症模型，载脂蛋白e缺乏（Apoe - / -）小鼠中确定了Fn-EDA在卒中预后中的作用。在短暂性脑缺血/再灌注损伤模型中，表达EDA中Fn缺陷的Apoe−/−小鼠（Fn-EDA−/−Apoe−/−小鼠）在第1天和第8天表现出较小的梗死和改善的神经预后（与Apoe−/−小鼠相比P<0.05）。同时，Fn-EDA - / - Apoe - / -小鼠脑内血栓形成（以纤维蛋白（原）沉积评估）和缺血后炎症（磷酸化nf -κB p65、磷酸化IKKα/β、il - 1-β和TNFα）明显减少（与Apoe - / -小鼠相比，P<0.05）。在FeCl3损伤诱导的颈动脉血栓形成模型中，Fn-EDA - / - Apoe - / -小鼠的血栓生长速度和闭塞时间延长（与Apoe - / -小鼠相比P<0.05）。基因消融TLR4可改善Apoe−/−小鼠的脑卒中预后（P<0.05），但对Fn-EDA−/−Apoe−/−小鼠的脑卒中预后无影响。骨髓移植实验显示，非造血细胞来源的Fn-EDA通过造血细胞上表达的TLR4加重脑卒中。在Apoe−/−小鼠再灌注后15分钟输注特定的Fn-EDA抑制剂可显著改善卒中预后。缺乏Fn-EDA的高胆固醇血症小鼠在缺血/再灌注损伤后脑血栓形成减少，炎症反应减轻。这些发现表明，靶向Fn-EDA可能是治疗卒中合并高胆固醇血症的有效策略。
The fibronectin splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts in the plasma of healthy humans, but markedly elevated in patients with comorbid conditions including diabetes and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes in such conditions. We determined the role of Fn-EDA in stroke outcome in a model of hypercholesterolemia, the apolipoprotein E-deficient (Apoe−/−) mouse. In a transient cerebral ischemia/reperfusion injury model, Apoe−/− mice expressing Fn deficient in EDA (Fn-EDA−/−Apoe−/− mice) exhibited smaller infarcts and improved neurological outcomes at days 1 and 8 (P<0.05 vs. Apoe−/− mice). Concomitantly, intracerebral thrombosis (assessed by fibrin (ogen) deposition) and postischemic inflammation (phospho-NF-κB p65, phospho IKKα/β, IL1-β and TNFα) within lesions of Fn-EDA−/−Apoe−/− mice were markedly decreased (P<0.05 vs. Apoe−/− mice). In a FeCl3 injury-induced carotid artery thrombosis model, thrombus growth rate and the time to occlusion were prolonged in Fn-EDA−/−Apoe−/− mice (P<0.05 vs. Apoe−/− mice). Genetic ablation of TLR4 improved stroke outcome in Apoe−/− mice (P<0.05) but had no effect on stroke outcome in Fn-EDA−/−Apoe−/− mice. Bone marrow transplantation experiments revealed that non-hematopoietic cell-derived Fn-EDA exacerbates stroke through TLR4 expressed on hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA into Apoe−/− mouse 15 minutes after reperfusion significantly improved stroke outcome. Hypercholesterolemic mice deficient in Fn-EDA exhibit reduced cerebral thrombosis and less inflammatory response after ischemia/reperfusion injury. These findings suggest that targeting Fn-EDA could be an effective therapeutic strategy in stroke associated with hypercholesterolemia.