Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice.
BACKGROUND
Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity.


RESULTS
Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression.


CONCLUSIONS
TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.
Riad
Alexander
A
Charité - Universitätsmedizin Berlin, Germany, Campus Benjamin Franklin, Department of Cardiology and Pneumology, Hindenburgdamm 30, 12200 Berlin, Germany.
Bien
Sandra
S
Gratz
Matthias
M
Escher
Felicitas
F
Westermann
Dirk
D
Heimesaat
Markus M
MM
Bereswill
Stefan
S
Krieg
Thomas
T
Felix
Stephan B
SB
Schultheiss
Heinz P
HP
Kroemer
Heyo K
HK
Tschöpe
Carsten
C
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D004317:Doxorubicin / Q000009:adverse effects; D019332:Endothelin-1 / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000172:deficiency*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D000903:Antibiotics, Antineoplastic; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin