Toll-like receptor 4 mediates the inflammatory responses and matrix protein remodeling in remote non-ischemic myocardium in a mouse model of myocardial ischemia and reperfusion.
Toll-like receptor 4 mediates the inflammatory responses and matrix protein remodeling in remote non-ischemic myocardium in a mouse model of myocardial ischemia and reperfusion.
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DOI：
10.1371/journal.pone.0121853
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Zhai Y;Ao L;Cleveland JC;Zeng Q;Reece TB;Fullerton DA;Meng X
局部缺血/再灌注（I/R）后远端非缺血心肌中介导炎症反应的信号传导机制仍不完全清楚。心肌Toll样受体4（TLR 4）可被损伤细胞释放的多种蛋白激活，在心肌炎症和损伤扩展中发挥作用。我们验证了TLR 4在介导局部I/R损伤后远端非缺血心肌的炎症反应和基质蛋白重塑中发挥重要作用的假设。方法与结果：对TLR 4缺陷型（C3 H/HeJ）和TLR 4活性型（C3 H/HeN）小鼠进行冠状动脉结扎（30分钟）和再灌注1、3、7或14天。在TLR 4感受态小鼠中，在再灌注第1、3和7天，远端非缺血心肌中单核细胞趋化蛋白-1（MCP-1）、角质形成细胞趋化因子（KC）、细胞间粘附分子-1（ICAM-1）和血管细胞粘附分子-1（VCAM-1）的水平升高。在再灌注第7天和第14天，远端非缺血心肌中I型胶原、IV型胶原、基质金属蛋白酶（MMP）2和MMP 9的水平升高。MMP 2和MMP 9活性也升高。TLR 4缺乏导致心肌梗死面积中度减少。然而，它明显降低了远端非缺血心肌中趋化因子、粘附分子和基质蛋白水平的变化。此外，TLR 4缺陷小鼠在第14天的左心室功能显著改善。总之，TLR 4介导了局部心肌I/R损伤后远端非缺血心肌的炎症反应和基质蛋白重构，并参与了不良心脏重构的机制。
The signaling mechanism that mediates inflammatory responses in remote non-ischemic myocardium following regional ischemia/reperfusion (I/R) remains incompletely understood. Myocardial Toll-like receptor 4 (TLR4) can be activated by multiple proteins released from injured cells and plays a role in myocardial inflammation and injury expansion. We tested the hypothesis that TLR4 occupies an important role in mediating the inflammatory responses and matrix protein remodeling in the remote non-ischemic myocardium following regional I/R injury. Methods and results: TLR4-defective (C3H/HeJ) and TLR4-competent (C3H/HeN) mice were subjected to coronary artery ligation (30 min) and reperfusion for 1, 3, 7 or 14 days. In TLR4-competent mice, levels of monocyte chemoattractant protein -1 (MCP-1), keratinocyte chemoattractant (KC), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were elevated in the remote non-ischemic myocardium at day 1, 3, and 7 of reperfusion. Levels of collagen I, collagen IV, matrix metalloproteinase (MMP) 2 and MMP 9 were increased in the remote non-ischemic myocardium at day 7 and 14 of reperfusion. MMP 2 and MMP 9 activities were also increased. TLR4 deficiency resulted in a moderate reduction in myocardial infarct size. However, it markedly downgraded the changes in the levels of chemokines, adhesion molecules and matrix proteins in the remote non-ischemic myocardium. Further, left ventricular function at day 14 was significantly improved in TLR4-defective mice. In conclusion, TLR4 mediates the inflammatory responses and matrix protein remodeling in the remote non-ischemic myocardium following regional myocardial I/R injury and contributes to the mechanism of adverse cardiac remodeling.
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DOI：
10.1084/jem.20001858
发表时间：
2002-01-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Termeer C;Benedix F;Sleeman J;Fieber C;Voith U;Ahrens T;Miyake K;Freudenberg M;Galanos C;Simon JC
通讯作者：
Simon JC
影响因子：
37.8
作者：
Oyama, J;Blais, C;Bourcier, T
通讯作者：
Bourcier, T
影响因子：
6.2
作者：
Kaczorowski, David J.;Nakao, Atsunori;Billiar, Timothy R.
通讯作者：
Billiar, Timothy R.
DOI：
10.1152/ajpheart.00370.2004
发表时间：
2005-01-01
影响因子：
4.8
作者：
Ikonomidis, JS;Hendrick, JW;Spinale, FG
通讯作者：
Spinale, FG
影响因子：
3.8
作者：
Su, Xin;Sykes, Joshua B.;Ao, Lihua;Raeburn, Christopher D.;Fullerton, David A.;Meng, Xianzhong
通讯作者：
Meng, Xianzhong