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Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium
Stefan Frantz, … , Richard T. Lee, Ralph A. Kelly
Stefan Frantz, … , Richard T. Lee, Ralph A. Kelly
Published August 1, 1999
Citation Information: J Clin Invest. 1999;104(3):271-280. https://doi.org/10.1172/JCI6709.
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Article

Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium

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Abstract

Expression of innate immune response proteins, including IL-1β, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1β, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-κB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.

Authors

Stefan Frantz, Lester Kobzik, Young-Dae Kim, Ryuji Fukazawa, Ruslan Medzhitov, Richard T. Lee, Ralph A. Kelly

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Figure 9

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Immunohistochemical analysis of TLR4 in rat, murine, and human cardiac m...
Immunohistochemical analysis of TLR4 in rat, murine, and human cardiac muscle. Photomicrographs are shown for primary isolates of ventricular myocytes isolated from adult rat hearts (×400) 24 hours after isolation, stained with a polyclonal Toll antibody targeted to a TLR4-specific epitope adjacent to the cytoplasmic TIR domain of hTLR4. Absorption with the peptide used to generate the primary antibody (Anti-Toll + peptide) and substitution of the primary antibody with a control rabbit antiserum (Control serum) were used as controls. Both normal murine cardiac muscle (×200), as shown here, and sham-operated murine cardiac muscle and normal rat cardiac muscle (not shown) exhibited diffuse, homogeneous myocyte staining. However, cardiac myocytes adjacent to an area of ischemic injury (Infarct) in the mouse exhibited intense sarcolemmal staining for TLR4. Note the absence of significant staining of infiltrating inflammatory cells (×400). Finally, in samples from both humans with a dilated cardiomyopathy (bottom left panel) and in remodeling murine ventricular muscle remote from the site of ischemic injury (not shown), intensely stained focal expression of TLR4 was observed in adjacent regions of 2 or more juxtaposed cardiac myocytes (×600). This intense focal staining pattern for TLR4 was not observed in sections of normal human myocardium (not shown).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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