title: Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice.
abstract: BACKGROUND
  Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin) induced cardiac toxicity. 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 signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity.
  
  
  METHODS
  Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+) and HeJ mutant (TLR4-/-) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker.
  
  
  RESULTS
  Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 -/-; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4-/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN).
  
  
  CONCLUSIONS
  Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.
authors: University of Colorado Denver, Department of Medicine and Surgery, Aurora, CO 80045, USA. nasser.alemeerat@ucdenver.edu
authors: Nasser Ghaly
authors: NG
authors: Yousif
authors: Fadhil G
authors: FG
authors: Al-Amran
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D002302:Cardiac Output / Q000235:genetics / Q000276:immunology; D054715:Cardiotoxins / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009205:Myocarditis; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054715:Cardiotoxins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000068878:Trastuzumab