Toll‐like receptor 4 modulates myocardial ischaemia–reperfusion injury: Role of matrix metalloproteinases

Abstract

Toll-like receptor 4 (TLR4) mediates innate immune responses following endotoxemia and myocardial ischaemia -reperfusion (I/R) injury. Pre-treatment with the major TLR4 ligand lipopolysaccharide (LPS) reduces infarct size. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play a crucial role in endotoxemia possibly also determining I/R injury. Aims: We investigated the influence of TLR4 on infarct size and assessed the influence of MMP and TIMP regulation on I/R injury. Methods: Left anterior descending artery (LAD) occlusion was performed on wild-type (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice. Animals were stimulated with LPS (1 mg/kg) or PBS 16 h ahead of 60 min LAD ligation. After 24 h of reperfusion, triphenyltetrazolium chloride staining was performed and infarct size was measured by planimetry. MMP-and TIMP-mRNA expression were determined by RPA after 3 h of reperfusion. MMP zymographic activity was monitored 6 h after occlusion. Results: TLR4-deficient mice and LPS-treated wild-type mice showed significantly reduced infarct areas. LPS-stimulation significantly increased the overall MMP/TIMP mRNA expression ratio due to elevated MMP-3, -8, -9, and TIMP-1 in wild-type mice. I/R overall reduced the MMP/TIMP ratio due to increased MMP-1, TIMP-1, and -3 mRNA expression. Conclusions: LPS pre-treatment and TLR4-deficiency led to a decreased infarct size. However, infarct area and MMP/TIMP ratio were not correlated. This means that in TLR4-deficient mice MMP/TIMP ratios are not determining the infarct size.

TRIF Is a Critical Survival Factor in Viral Cardiomyopathy

“…In contrast, TRIF deficiency under those conditions led to a reduced LV function after viral infection, which subsequently resulted in a heart rateindependent cardiac output decrease of ∼53% when compared with noninfected TRIF 2/2 mice. Whereas other members of the TLR system, namely TLR2, TLR4, TLR9, and MyD88, have been shown to induce a decrease of contractility in different experimental models of heart failure and in myocyte cell culture, our study demonstrates protective effects of TRIF and therefore a new physiological role at least in regard to a distinct part of the cardiac TLR system (17,18,(32)(33)(34)(35)(36)(37)(38)(39).…”

Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

“…Until today, current data suggested a role for TLR2 and TLR4 in the development of several types of heart failure, whereas other members of the TLR family do not appear to have been studied in regard to such conditions (8,31). TLR4 has recently attracted considerable attention from studies in KO mice showing that this receptor is able to sufficiently trigger on pressure overload-induced concentric hypertrophy as well as on infarct size and survival due to ischemia/reperfusion injury (9,16,(32)(33)(34). However, the ischemia/reperfusion model differs in comparison with the model of chronic ischemic cardiomyopathy induced after permanent occlusion of the left anterior descending artery.…”

Ischemia–reperfusion and immediate T cell responses

“…TLRs are primarily expressed in antigen presenting cells (APCs) and are also present on endothelial and stromal cells [68][69][70]. TLR4 deficient mice were protected from IRI of lung, liver, heart and brain, implicating the role of TLR4 in the initiation of IRI [71][72][73][74][75]. In the kidney, both TLR2 and TLR4 expression were increased after IRI [76], and TLR2 KO mice exhibited attenuated renal injury after IRI [77].…”