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.

Yufeng Zhai,Qingchun Zeng,David A Fullerton,Xianzhong Meng,Lihua Ao,T Brett Reece,Joseph C Cleveland,John Calvert

doi:10.1371/journal.pone.0121853

Yufeng Zhai, Qingchun Zeng + Show 6 more

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https://doi.org/10.1371/journal.pone.0121853

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Abstract

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.

Highlights

Ischemic heart disease remains the major cause of morbidity and mortality
monocyte chemoattractant protein -1 (MCP-1) and keratinocyte chemoattractant (KC) levels in ischemic myocardium of Toll-like receptor 4 (TLR4)-competent mice increased after 1 day of reperfusion and reached to peak levels after 3 days of reperfusion (Fig. 2A)
In the remote non-ischemic myocardial tissue. The levels of these inflammatory mediators in non-ischemic myocardium are much lower in TLR4-defective mice in comparison to those in TLR4-competent mice. These results demonstrate that the remote nonischemic myocardium has sustained inflammatory responses to an ischemia and reperfusion (I/R) insult and that TLR4 is involved in mediating these responses

Summary

Introduction

Toll-like receptor 4 (TLR4) has been found to play a role in myocardial I/R injury in both regional and global I/R models [2,3,4]. Activation of this innate immunoreceptor by a variety of endogenous agents, termed as danger-associated molecular patterns (DAMPs), leads to the activation of pro-inflammatory signaling cascades. While the role of TLR4 in myocardial I/R injury following a short term of reperfusion has been extensively evaluated [2], [3], [11], few studies have determined the role of TLR4 in myocardial I/R injury and cardiac function in a prolonged time course

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