title: 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.
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.
  
  
  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.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America; Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020782:Matrix Metalloproteinases
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