The HMGB1-TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis.

Toll-like receptor 4 (TLR4) and its ligand high mobility group box 1 (HMGB1), are known for playing central roles in ischemia-reperfusion injury in myocardium. However, the detailed mechanisms of TLR4 and HMGB1 are not fully understood. The aim of this study was to investigate the effects and possible mechanisms of the HMGB1-TLR4 axis and cardiomyocyte apoptosis on myocardial ischemic damage. Artificial oxygen ventilated anesthetized C3H/HeN mice and C3H/HeJ mice were subjected to 30 min of left anterior descending coronary artery occlusion followed by 6h of reperfusion. The myocardial infarct size, HMGB1 levels, apoptosis index, Bax, Bcl-2 and TNF-α mRNA levels were assessed. The results showed that a lowered amount of cardiomyocyte apoptosis and infarct size in the myocardium of TLR4-mutant mice after myocardial I/R and that TLR4 deficiency notably inhibited the expression of HMGB1 and TNF-a, both of which were up-regulated by ischemia/reperfusion. These findings suggest that the HMGB1-TLR4 axis plays a pathogenic role in triggering cardiomyocyte apoptosis during myocardial I/R injury and that the possible mechanism for this process is the result of released cytokines and inflammatory response involved in the HMGB1/TLR4-related pathway.

Ding HS ，Yang J ，Chen P ，Yang J ，Bo SQ ，Ding JW ，Yu QQ ... -  《-》

High mobility group [corrected] box 1 mediates neutrophil recruitment in myocardial ischemia-reperfusion injury through toll like receptor 4-related pathway.

This study aimed to explore the role of high mobility group [corrected] box 1 (HMGB1) and its receptor toll like receptor 4 (TLR4) on neutrophils in myocardial ischemia reperfusion (I/R) injury. We constructed TLR4-mutant (C3H/HeJ) and control (C3H/HeN) mouse models of myocardial I/R injury and subjected the mice to 30 min of ischemia and 6h of reperfusion. Light microscope was used to observe structural changes in the myocardium. HMGB1 levels were measured using quantitative real-time PCR and immunohistochemistry. Neutrophil accumulation, TNF-a expression and IL-8 levels were analyzed via myeloperoxidase (MPO) biochemical studies, quantitative real-time PCR and ELISA, respectively. The results demonstrated that fewer neutrophils infiltrated in the myocardium of TLR4-mutant mice after myocardial I/R and that TLR4 deficiency markedly decreased the ischemic injury caused by ischemia/reperfusion, and inhibited the expression of HMGB1, TNF-a, and IL-8, all of which were up-regulated by ischemia/reperfusion. These findings suggest that HMGB1 plays a central role in recruiting neutrophils during myocardial I/R leading to worsened myocardial I/R injury. This recruitment mechanism is possibly due to its inflammatory and chemokine functions based on the TLR4-dependent pathway.

Ding HS ，Yang J ，Gong FL ，Yang J ，Ding JW ，Li S ，Jiang YR ... -  《-》

Fluvastatin attenuated ischemia/reperfusion-induced autophagy and apoptosis in cardiomyocytes through down-regulation HMGB1/TLR4 signaling pathway.

Ding HS ，Yang J ，Yang J ，Guo X ，Tang YH ，Huang Y ，Chen Z ，Fan ZX ，Huang CX ... -  《-》

Alpha-lipoic acid impedes myocardial ischemia-reperfusion injury, myocardial apoptosis, and oxidative stress by regulating HMGB1 expression.

Inflammation, oxidative stress, and apoptosis contribute to myocardial ischemia/reperfusion injury (I/RI). Alpha-lipoic acid (ALA) plays a critical role in I/RI by impeding apoptosis and inflammation. Here, we aimed to explore the underlying mechanisms of ALA after I/RI. The left anterior descending coronary artery (LAD) was ligated, and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish an I/RI model. Prior to this, H9c2 cells and rats were treated using an appropriate amount of ALA. The cardiac function, inflammatory factors, and myocardial pathology were assessed in vitro. We detected cell viability, apoptosis, and oxidative stress-related factors in vivo. Moreover, proteins of the HMGB1/TLR4/NF-κB signaling pathway were detected both in vivo and in vitro. We observed that ALA increased cell viability in vitro and decreased apoptosis in vitro and in vivo. ALA inhibited reactive oxygen species production, decreased malondialdehyde, and increased superoxide dismutase activity to resist oxidative stress in vitro. ALA also reduced the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-α) in vivo. ALA also suppressed the levels of the apoptotic protein, Bax, and increased the expression of the anti-apoptotic protein Bcl-2, in vitro and in vivo. Moreover, we observed that ALA significantly inhibited the cytoplasmic localization of HMGB1, which might attenuate MI/RI or H/R via HMGB1/TLR4/NF-κB pathway. ALA regulates HMGB1 translocation and attenuates I/R via the HMGB1/TLR4/NF-κB signaling pathway, thus impeding apoptosis, oxidation, and inflammation, and might be a potential target for myocardial ischemia/reperfusion injury.

Qi B ，Zheng Y ，Gao W ，Qi Z ，Gong Y ，Liu Y ，Wang Y ，Cheng X ，Ning M ，Lang Y ，Feng J ，Li T ... -  《-》

TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion.

Splanchnic ischemia is common in critically ill patients, and it can result in injury not only of the intestine but also in distant organs, particularly in the lung. Local inflammatory changes play a pivotal role in the development of acute lung injury after intestinal ischemia, but the underlying molecular mechanisms are not fully understood. We sought to examine the role of Toll-like receptor 4 (TLR4) in the mouse model of intestinal ischemia-reperfusion (I/R)-induced lung injury and inflammation. Adult male TLR4 mutant (C3H/HeJ) mice and TLR4 wild-type (WT) (C3H/HeOuJ) mice were subjected to 40 min of intestinal ischemia by clamping the superior mesenteric artery followed by 6 h of reperfusion. Lung histology was assessed and parameters of pulmonary microvascular permeability, inflammatory cytokine expression, and neutrophil infiltration were measured. Activation of mitogen-activated protein kinases (MAPKs) and the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in the lungs were also detected. After intestinal I/R, lungs from TLR4 mutant mice demonstrated a significantly lower histological injury, a marked reduction of epithelial apoptosis associated with the decreased level of cleaved caspase-3 and the increased ratio of Bcl-xL to Bax proteins, and a large reduction in pulmonary vascular permeability and myeloperoxidase (MPO) activity in comparison with WT mice. TLR4 mutant mice also displayed marked decreases in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) expression. Following intestinal I/R, phosporylation of p38 MAPK and activation of NF-κB and AP-1 were significantly inhibited in lung tissue from TLR4 mutant mice compared with WT controls. These data suggest that TLR4 plays an important role in the pathogenesis of intestinal I/R-induced acute lung injury and inflammation and that p38 kinase and NF-κB may be involved in TLR4 signaling-mediated lung inflammatory processes during intestinal I/R.

Ben DF ，Yu XY ，Ji GY ，Zheng DY ，Lv KY ，Ma B ，Xia ZF ... -  《-》