PMID- 19448144
OWN - NLM
STAT- MEDLINE
DCOM- 20090812
LR  - 20220311
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 297
IP  - 1
DP  - 2009 Jul
TI  - Myocardial TLR4 is a determinant of neutrophil infiltration after global 
      myocardial ischemia: mediating KC and MCP-1 expression induced by extracellular 
      HSC70.
PG  - H21-8
LID - 10.1152/ajpheart.00292.2009 [doi]
AB  - Cardiac surgery with global myocardial ischemia-reperfusion (I/R) induces a 
      myocardial inflammatory response that impairs cardiac recovery. Chemokines 
      contribute to the overall myocardial inflammatory response through inducing 
      leukocyte infiltration. Although Toll-like receptor 4 (TLR4) has an important 
      role in postischemic myocardial injury, the relative roles of myocardial tissue 
      and leukocyte TLR4 in leukocyte infiltration, as well as the role of TLR4 in 
      myocardial chemokine expression, are unclear. Our recent study, in an isolated 
      mouse heart model of global I/R, found that the 70-kDa heat shock cognate protein 
      (HSC70) is released from cardiac cells and mediates the expression of 
      cardiodepressant cytokines via a TLR4-dependent mechanism. In the present study, 
      we tested the hypotheses that myocardial tissue TLR4 has a major role in 
      mediating neutrophil infiltration and that myocardial TLR4 and extracellular 
      HSC70 contribute to the mechanisms underlying cardiac chemokine response to 
      global I/R. We subjected hearts isolated from TLR4-defective and TLR4-competent 
      mice to global I/R and examined myocardial neutrophil infiltration and expression 
      of keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1 
      (MCP-1). TLR4-defective hearts exhibited reduced neutrophil infiltration 
      regardless of the phenotypes of neutrophils perfused during reperfusion and 
      expressed lower levels of KC and MCP-1. HSC70-specific antibody reduced 
      myocardial expression of KC and MCP-1 after I/R. Furthermore, perfusion of HSC70 
      increased KC and MCP-1 expression in TLR4-competent hearts but not in 
      TLR4-defective hearts, and HSC70 also induced the chemokine response in 
      macrophages in a TLR4-dependent fashion. A recombinant HSC70 fragment lacking the 
      substrate-binding domain was insufficient to induce chemokine expression in 
      hearts and cells. This study demonstrates that myocardial tissue TLR4, rather 
      than neutrophil TLR4, is the determinant of myocardial neutrophil infiltration 
      after global I/R. TLR4 mediates myocardial chemokine expression, and the 
      mechanisms involve extracellular HSC70. These results imply the HSC70-TLR4 
      interaction as a novel mechanism underlying the myocardial chemokine response to 
      global I/R.
FAU - Ao, Lihua
AU  - Ao L
AD  - Department of Surgery, University of Colorado Denver, Aurora, CO 80045, USA.
FAU - Zou, Ning
AU  - Zou N
FAU - Cleveland, Joseph C Jr
AU  - Cleveland JC Jr
FAU - Fullerton, David A
AU  - Fullerton DA
FAU - Meng, Xianzhong
AU  - Meng X
LA  - eng
GR  - R01 HL079051/HL/NHLBI NIH HHS/United States
GR  - HL-079051/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090515
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (HSC70 Heat-Shock Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Toll-Like Receptor 4)
RN  - 147037-79-4 (keratinocyte-derived chemokines)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/genetics/*physiology
MH  - Chemokines/genetics/*physiology
MH  - Extracellular Space/physiology
MH  - Fluorescent Antibody Technique
MH  - HSC70 Heat-Shock Proteins/*pharmacology
MH  - Heart/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Myocardial Ischemia/*physiopathology
MH  - Myocardium/*metabolism
MH  - Neutrophil Infiltration/*physiology
MH  - Recombinant Proteins/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Toll-Like Receptor 4/*physiology
PMC - PMC2711729
EDAT- 2009/05/19 09:00
MHDA- 2009/08/13 09:00
PMCR- 2010/07/01
CRDT- 2009/05/19 09:00
PHST- 2009/05/19 09:00 [entrez]
PHST- 2009/05/19 09:00 [pubmed]
PHST- 2009/08/13 09:00 [medline]
PHST- 2010/07/01 00:00 [pmc-release]
AID - 00292.2009 [pii]
AID - H-00292-2009 [pii]
AID - 10.1152/ajpheart.00292.2009 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H21-8. doi: 
      10.1152/ajpheart.00292.2009. Epub 2009 May 15.