title: The HMGB1-TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis.
abstract: 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.
authors.affiliation: Institute of Cardiovascular Diseases, China Three Gorges University, 443000 Yichang, Hubei Province, China.
authors.forename: Hua-Sheng
authors.initials: HS
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Sun-Qing
authors.initials: SQ
authors.lastname: Bo
authors.forename: Jia-Wang
authors.initials: JW
authors.lastname: Ding
authors.forename: Qin-Qin
authors.initials: QQ
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015870:Gene Expression; D024243:HMGB1 Protein / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse
keywords: AAR; AI; AMI; ANOVA; Apoptosis; ECL; HMGB1; High mobility group box 1; I/R; JNKs; LAD; Myocardial ischemia/reperfusion injury; NF-κB; PCR; RAGE; TLR4; TNF-α; Toll-like receptor 4; Tumor necrosis factor-α; acute myocardial infarction; apoptosis index; c-Jun N-terminal kinases; enhanced chemiluminescence; high mobility group box 1; ischemia/reperfusion; left anterior descending coronary artery; nuclear factor kappa B; one-way analysis of variance; polymerase chain reaction; receptor for advanced glycation end products; the area at risk; toll-like receptor 4; tumor necrosis factor-α