Toll-like receptor 4 deficiency: smaller infarcts, but no gain in function.
BACKGROUND
It has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac function. In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).


RESULTS
Infarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 +/- 4.2 mmHg vs. 77.9 +/- 1.7 mmHg in WT, p < 0.05). Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p < 0.05). C3H/HeJ MI/R showed increased myocardial IL-1beta and IL-6 expression compared to their respective shams (p < 0.05), indicating TLR4-independent cytokine activation due to MI/R.


CONCLUSIONS
These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it does not preserve myocardial function. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.
Kim
Se-Chan
SC
Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Germany. sckkim@ucdavis.edu <sckkim@ucdavis.edu>
Ghanem
Alexander
A
Stapel
Heidi
H
Tiemann
Klaus
K
Knuefermann
Pascal
P
Hoeft
Andreas
A
Meyer
Rainer
R
Grohé
Christian
C
Knowlton
Anne A
AA
Baumgarten
Georg
G
D000818:Animals; D016207:Cytokines / Q000097:blood*; D006321:Heart / Q000503:physiopathology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology*; D009929:Organ Size; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4