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Toll‐like receptor‐4 deficiency attenuates doxorubicin‐induced cardiomyopathy in mice
Author(s) -
Riad Alexander,
Bien Sandra,
Gratz Matthias,
Escher Felicitas,
Heimesaat Markus M.,
Bereswill Stefan,
Krieg Thomas,
Felix Stephan B.,
Schultheiss Heinz P.,
Kroemer Heyo K.,
Tschöpe Carsten
Publication year - 2008
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1016/j.ejheart.2008.01.004
Subject(s) - medicine , tlr4 , oxidative stress , cardiotoxicity , inflammation , cardiac function curve , heart failure , diabetic cardiomyopathy , cardiomyopathy , endocrinology , receptor , apoptosis , dilated cardiomyopathy , doxorubicin , pathophysiology , pharmacology , chemotherapy , biology , biochemistry
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. Methods and 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‐α 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.