title: Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice.
abstract: BACKGROUND
  Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction.
  
  
  RESULTS
  Cardiac dysfunction was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and TLR-2-knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice (P<0.01). Nuclear factor-kappaB activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice (P<0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice (P<0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%, P<0.05).
  
  
  CONCLUSIONS
  These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.
authors.affiliation: First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nozaki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases