Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice
Kessler, Elise L.; Wang, Jiong Wei; Kok, Bart; Brans, Maike A.; Nederlof, Angelique; van Stuijvenberg, Leonie; Huang, Chenyuan; Vink, Aryan; Arslan, Fatih; Efimov, Igor R.; Lam, Carolyn S.P.; Vos, Marc A.; de Kleijn, Dominique P.V.; Fontes, Magda S.C.; van Veen, Toon A.B.
(2021) International journal of molecular sciences, volume 22, issue 21, pp. 1 - 13
(Article)
Abstract
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
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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 (n = 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, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 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, p < 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, p = 0.005). Our data suggest that TLR2 deficiency exacerbates 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.
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Keywords: Heart failure, Inflammation, Pressure overload, TLR2, TLR4, Toll-like receptors, Blood Pressure, Toll-Like Receptor 4/genetics, Heart Ventricles/metabolism, Male, Toll-Like Receptor 2/genetics, Mice, Knockout, Ventricular Remodeling, Animals, Mice, Cardiomegaly/metabolism, Molecular Biology, Spectroscopy, Catalysis, Inorganic Chemistry, Computer Science Applications, Physical and Theoretical Chemistry, Organic Chemistry, Journal Article
ISSN: 1661-6596
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: Funding: This research was funded by the Netherlands CardioVascular Research Initiative: The Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT to E.L.K., L.v.S., M.A.V., T.A.B.v.V., and M.S.C.F.). Moreover, it was supported by the National Medical Research Council of Singapore (CS-IRG13nov024 to CSPL and DPVdK), the ATTRaCT grant (SPF2014/003 to C.S.P.L. and D.P.V.d.K.), the Royal Netherlands Academy of Arts and Sciences (KNAW) Strategic grant (to D.P.V.d.K.) and the National University Health System collaborative grant (NUHS O-CRG 2016 Oct-23 to J.-W.W.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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