Toll‐like Receptor 4 (TLR4) Knock‐out Mice Are Partially Protected from Diabetic Bladder Dysfunction

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

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Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via TRAF/MAPK signaling pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/015-2/423-432 ◽

2015 ◽

Vol 2 (3) ◽

pp. 423-432

Keyword(s):

Mapk Signaling ◽

Lv Function ◽

Toll Like Receptor ◽

Cardiac Damage ◽

Male Adult ◽

Knock Out ◽

Monocyte Chemoattractant Protein 1 ◽

Novel Approach ◽

Heart Injury ◽

Knock Out Mice

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

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Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via TRAF/MAPK signaling pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/015-02/413-422 ◽

2015 ◽

Vol 2 (3) ◽

pp. 423-432

Author(s):

Robyn Wonder ◽

Steliana Penzkofer ◽

Evelyn G Hazen

Keyword(s):

Mapk Signaling ◽

Lv Function ◽

Toll Like Receptor ◽

Cardiac Damage ◽

Male Adult ◽

Knock Out ◽

Monocyte Chemoattractant Protein 1 ◽

Novel Approach ◽

Heart Injury ◽

Knock Out Mice

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

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Abstract 201: Mice Lacking the Gene for Toll-like Receptor 4 (TLR4) Had an Attenuated ER Stress in the Heart in Response to Ang II Infusion

Hypertension ◽

10.1161/hyp.62.suppl_1.a201 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Rahul Dange ◽

Anand R. Nair ◽

Jorge Vila ◽

Philip J Ebenezer ◽

Joseph Francis

Keyword(s):

Cardiac Hypertrophy ◽

Er Stress ◽

Left Ventricular ◽

Ang Ii ◽

Toll Like Receptor ◽

Wild Type ◽

Rt Pcr ◽

Toll Like Receptor 4 ◽

Knock Out ◽

The Brain

Inflammatory molecule plays an important role in the pathophysiology of hypertension. Recently we showed that TLR4 inhibition in the brain attenuates hypertension. In this study we demonstrate that ANGII induced ER stress in the heart is attenuated in mice lacking the gene for TLR4. In addition, we show that ANGII induced cardiac hypertrophy is blocked by ER stress inhibitor. Method: TLR4 knock-out (KO) mice and wild type (WT) controls were implanted with telemetry probes for mean arterial pressure (MAP) measurements. After collecting baseline MAP and left ventricular function using echocardiography, osmotic minipump containing ANGII (200ng/kg/min) or vehicle (saline) was implanted for 14 days. In another group, C57BL6 mice were injected with ER stress inhibitor 4-PBA (150mg/kg bw) given intraperitoneally with and without ANGII. At the end of the study, mice were sacrificed the LV tissue removed and analyzed for gene of interest using RT-PCR and Western blotting. Results are tabulated. The real-time PCR values are shown as αCT values (18S - the gene of interest). Conclusions: 1) ANGII infusion induces cardiac hypertrophy and ER stress. 2) Mice lacking the gene for TLR4 had attenuated cardiac hypertrophy and ER stress in response to ANGII. 3) ER stress inhibitor protect against ANGII induces cardiac hypertrophy. 4) TLR4 at least in part contributes to ANG II induced cardiac hypertrophy and ER stress.

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