Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation.
Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation.
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DOI：
10.1055/s-0038-1661353
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发表时间：
2018-08
影响因子：
6.7
通讯作者：
Chauhan AK
中科院分区：
文献类型：
--
作者：
Chorawala MR;Prakash P;Doddapattar P;Jain M;Dhanesha N;Chauhan AK
含有额外结构域A的纤连蛋白剪接变体（Fn-EDA）是toll样受体4（TLR 4）的内源性配体，其在健康人血浆中以可忽略的量存在，但在患有包括糖尿病和高脂血症的共病病症（其是心肌梗死（MI）的危险因素）的患者中显著升高。在这些共病条件下，Fn-EDA在急性MI病理生理学中的作用知之甚少。我们确定了Fn-EDA在高脂血症载脂蛋白E缺陷（Apoe-/-）小鼠心肌缺血/再灌注（I/R）损伤中的作用。在心肌I/R损伤模型（1小时缺血/ 23小时再灌注）中评估了心肌细胞大小、血浆心肌肌钙蛋白I（cTnI）水平、血管内血栓形成（CD 41阳性）、中性粒细胞浸润（Ly 6 B.2阳性）、中性粒细胞胞外陷阱（瓜氨酸化H3阳性）和心肌细胞凋亡（TUNEL阳性）。无论性别如何，Fn-EDA−/−Apoe−/−小鼠均表现出较小的梗死面积和cTnI水平降低，同时缺血后血管内血栓、中性粒细胞内流、中性粒细胞胞外陷阱和心肌细胞凋亡减少（与Apoe−/−小鼠相比，P<0.05）。TLR 4基因缺失可减轻Apoe−/−小鼠的心肌I/R损伤（与Apoe−/−小鼠相比P<0.05），但在Fn-EDA−/− Apoe−/−小鼠中并未进一步减轻，表明Fn-EDA需要TLR 4介导心肌I/R损伤。骨髓移植实验表明，Fn-EDA通过在造血细胞上表达TLR 4加重心肌I/R损伤。在再灌注后15分钟，将Fn-EDA的特异性抑制剂输注到Apoe−/−小鼠中，减轻了心肌I/R损伤。Fn-EDA通过促进缺血后血栓炎症反应加重TLR 4依赖性心肌I/R损伤。靶向Fn-EDA可减少急性MI后冠状动脉再通后的心脏损伤。
Fibronectin splicing variant containing extra domain A (Fn-EDA), which is an endogenous ligand for toll-like-receptor 4 (TLR4), is present in negligible amounts in the plasma of healthy humans, but markedly elevated in patients with comorbid conditions including diabetes and hyperlipidemia, which are risk factors for myocardial infarction (MI). Very little is known about the role of Fn-EDA in the pathophysiology of acute MI under these comorbid conditions. We determined the role of Fn-EDA in myocardial ischemia/reperfusion (I/R) injury in the hyperlipidemic apolipoprotein E-deficient (Apoe−/−) mice. Infarct size, plasma cardiac troponin I (cTnI) levels, intravascular thrombosis (CD41-positive), neutrophil infiltration (Ly6 B.2-positive), neutrophil extracellular traps (citrullinated H3-positive) and myocyte apoptosis (TUNEL-positive) were assessed in myocardial I/R injury model (1-hour ischemia/ 23 hours of reperfusion). Irrespective of gender, Fn-EDA−/−Apoe−/− mice exhibited smaller infarct size and decreased cTnI levels concomitant with reduced postischemic intravascular thrombi, neutrophils influx, neutrophil extracellular traps and myocyte apoptosis (P<0.05 vs. Apoe−/− mice). Genetic deletion of TLR4 attenuated myocardial I/R injury in Apoe−/− mice (P<0.05 vs. Apoe−/− mice), but did not further reduce in Fn-EDA−/− Apoe−/− mice suggesting that Fn-EDA requires TLR4 to mediate myocardial I/R injury. Bone marrow transplantation experiments revealed that Fn-EDA exacerbates myocardial I/R injury through TLR4 expressed on the hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA, 15 minutes post-reperfusion, into Apoe−/− mice attenuated myocardial I/R injury. Fn-EDA exacerbates TLR4-dependent myocardial I/R injury by promoting postischemic thrombo-inflammatory response. Targeting Fn-EDA may reduce cardiac damage following coronary artery recanalization after acute MI.
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影响因子：
8.3
作者：
Khan MM;Gandhi C;Chauhan N;Stevens JW;Motto DG;Lentz SR;Chauhan AK
通讯作者：
Chauhan AK
影响因子：
20.3
作者：
Prakash, Prem;Kulkarni, Paresh P.;Chauhan, Anil K.
通讯作者：
Chauhan, Anil K.
影响因子：
4.8
作者：
Okamura, Y;Watari, M;Strauss, JF
通讯作者：
Strauss, JF
影响因子：
37.8
作者：
Oyama, J;Blais, C;Bourcier, T
通讯作者：
Bourcier, T
影响因子：
37.8
作者：
LITT, MR;JEREMY, RW;BECKER, LC
通讯作者：
BECKER, LC