Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice

Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigat...

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Autores principales:	Elise L. Kessler, Jiong-Wei Wang, Bart Kok, Maike A. Brans, Angelique Nederlof, Leonie van Stuijvenberg, Chenyuan Huang, Aryan Vink, Fatih Arslan, Igor R. Efimov, Carolyn S. P. Lam, Marc A. Vos, Dominique P. V. de Kleijn, Magda S. C. Fontes, Toon A. B. van Veen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	toll-like receptors TLR2 TLR4 heart failure pressure overload inflammation Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ba8d61b686094645bdc5db31469aedd9
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spelling	oai:doaj.org-article:ba8d61b686094645bdc5db31469aedd92021-11-11T17:15:35ZVentricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice10.3390/ijms2221118231422-00671661-6596https://doaj.org/article/ba8d61b686094645bdc5db31469aedd92021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11823https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (<i>n</i> = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, <i>p</i> < 0.05), increased contractility (QRS and QTc, <i>p</i> < 0.05), and less inflammation (e.g., interleukins 6 and 1β, <i>p</i> < 0.05) after TAC compared to WT animals (<i>n</i> = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, <i>p</i> < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, <i>p</i> = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.Elise L. KesslerJiong-Wei WangBart KokMaike A. BransAngelique NederlofLeonie van StuijvenbergChenyuan HuangAryan VinkFatih ArslanIgor R. EfimovCarolyn S. P. LamMarc A. VosDominique P. V. de KleijnMagda S. C. FontesToon A. B. van VeenMDPI AGarticletoll-like receptorsTLR2TLR4heart failurepressure overloadinflammationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11823, p 11823 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	toll-like receptors TLR2 TLR4 heart failure pressure overload inflammation Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	toll-like receptors TLR2 TLR4 heart failure pressure overload inflammation Biology (General) QH301-705.5 Chemistry QD1-999 Elise L. Kessler Jiong-Wei Wang Bart Kok Maike A. Brans Angelique Nederlof Leonie van Stuijvenberg Chenyuan Huang Aryan Vink Fatih Arslan Igor R. Efimov Carolyn S. P. Lam Marc A. Vos Dominique P. V. de Kleijn Magda S. C. Fontes Toon A. B. van Veen Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
description	Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (<i>n</i> = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, <i>p</i> < 0.05), increased contractility (QRS and QTc, <i>p</i> < 0.05), and less inflammation (e.g., interleukins 6 and 1β, <i>p</i> < 0.05) after TAC compared to WT animals (<i>n</i> = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, <i>p</i> < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, <i>p</i> = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.
format	article
author	Elise L. Kessler Jiong-Wei Wang Bart Kok Maike A. Brans Angelique Nederlof Leonie van Stuijvenberg Chenyuan Huang Aryan Vink Fatih Arslan Igor R. Efimov Carolyn S. P. Lam Marc A. Vos Dominique P. V. de Kleijn Magda S. C. Fontes Toon A. B. van Veen
author_facet	Elise L. Kessler Jiong-Wei Wang Bart Kok Maike A. Brans Angelique Nederlof Leonie van Stuijvenberg Chenyuan Huang Aryan Vink Fatih Arslan Igor R. Efimov Carolyn S. P. Lam Marc A. Vos Dominique P. V. de Kleijn Magda S. C. Fontes Toon A. B. van Veen
author_sort	Elise L. Kessler
title	Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
title_short	Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
title_full	Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
title_fullStr	Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
title_full_unstemmed	Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
title_sort	ventricular tlr4 levels abrogate tlr2-mediated adverse cardiac remodeling upon pressure overload in mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ba8d61b686094645bdc5db31469aedd9
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Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice

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