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.
Institute of Cardiovascular Diseases, China Three Gorges University, Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, 443000 Yichang, Hubei Province, China.
Hua-Sheng
HS
Ding
Jun
J
Yang
Fei-Li
FL
Gong
Jian
J
Yang
Jia-Wang
JW
Ding
Song
S
Li
Yu-Rong
YR
Jiang
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D024243:HMGB1 Protein / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation
D016207:Cytokines; D017931:DNA Primers; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D016209:Interleukin-8; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha