Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure

Lena Bosch; Judith de Haan; Tom Seijkens; Claudia van Tiel; Maike Brans; Gerard Pasterkamp; Esther Lutgens; Saskia de Jager

doi:10.1016/j.ijcard.2018.12.076

Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure

Lena Bosch, Judith de Haan, Tom Seijkens, Claudia van Tiel, Maike Brans, Gerard Pasterkamp, Esther Lutgens, Saskia de Jager^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods & results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy.

Original language	English
Pages (from-to)	141-144
Number of pages	4
Journal	International Journal of Cardiology
Volume	279
DOIs	https://doi.org/10.1016/j.ijcard.2018.12.076
Publication status	Published - 15 Mar 2019
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020 , Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute .

Funding Information:
This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020, Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute.

Publisher Copyright:
© 2019 The Authors

Funding

This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020 , Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute . This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020, Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute.

Keywords

Animal models cardiovascular disease
Basic science research
Heart failure
Inflammation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijcard.2018.12.076Licence: CC BY-NC-ND

Cite this

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title = "Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure",

abstract = "Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods \& results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3\%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy.",

keywords = "Animal models cardiovascular disease, Basic science research, Heart failure, Inflammation",

author = "Lena Bosch and \{de Haan\}, Judith and Tom Seijkens and \{van Tiel\}, Claudia and Maike Brans and Gerard Pasterkamp and Esther Lutgens and \{de Jager\}, Saskia",

note = "Funding Information: This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020 , Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute . Funding Information: This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020, Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute. Publisher Copyright: {\textcopyright} 2019 The Authors",

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doi = "10.1016/j.ijcard.2018.12.076",

language = "English",

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T1 - Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure

AU - Bosch, Lena

AU - de Haan, Judith

AU - Seijkens, Tom

AU - van Tiel, Claudia

AU - Brans, Maike

AU - Pasterkamp, Gerard

AU - Lutgens, Esther

AU - de Jager, Saskia

N1 - Funding Information: This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020 , Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute . Funding Information: This work was supported by the UMC Utrecht Alexandre Suerman programme (L.B.). E.L. was supported by NWO (VICI), ERC consolidator grant, Horizon 2020, Deutsche Forschungsgemeinschaft (SFB 1123-project) and DZHK HRHV grant and T.S. by the Amsterdam cardiovascular research institute. Publisher Copyright: © 2019 The Authors

PY - 2019/3/15

Y1 - 2019/3/15

N2 - Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods & results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy.

AB - Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods & results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy.

KW - Animal models cardiovascular disease

KW - Basic science research

KW - Heart failure

KW - Inflammation

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DO - 10.1016/j.ijcard.2018.12.076

M3 - Article

C2 - 30612848

AN - SCOPUS:85059377453

SN - 0167-5273

VL - 279

SP - 141

EP - 144

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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