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Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice

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 ca...

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Autores principales: Yousif, Nasser Ghaly, Al-amran, Fadhil G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209438/
https://www.ncbi.nlm.nih.gov/pubmed/21999911
http://dx.doi.org/10.1186/1471-2261-11-62
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author Yousif, Nasser Ghaly
Al-amran, Fadhil G
author_facet Yousif, Nasser Ghaly
Al-amran, Fadhil G
author_sort Yousif, Nasser Ghaly
collection PubMed
description 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.
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spelling pubmed-32094382011-11-06 Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice Yousif, Nasser Ghaly Al-amran, Fadhil G BMC Cardiovasc Disord Research Article 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. BioMed Central 2011-10-14 /pmc/articles/PMC3209438/ /pubmed/21999911 http://dx.doi.org/10.1186/1471-2261-11-62 Text en Copyright ©2011 Yousif and Al-amran; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Yousif, Nasser Ghaly
Al-amran, Fadhil G
Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title_full Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title_fullStr Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title_full_unstemmed Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title_short Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
title_sort novel toll-like receptor-4 deficiency attenuates trastuzumab (herceptin) induced cardiac injury in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209438/
https://www.ncbi.nlm.nih.gov/pubmed/21999911
http://dx.doi.org/10.1186/1471-2261-11-62
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