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Article

The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling

1
Medical Clinics I—Cardiology and Angiology, Justus-Liebig-University, 35392 Giessen, Germany
2
German Center for Cardiovascular Research e.v. (DZHK), Partnersite RhineMain, 61231 Bad Nauheim, Germany
3
Kerckhoff Heart and Thorax Center, Department of Cardiology, 61231 Bad Nauheim, Germany
4
Department of Internal Medicine, Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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Murdoch Children’s Research Institute and Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children’s Hospital, Parkville, VIC 3052, Australia
6
Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, VIC 3052, Australia
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Department of Internal Medicine, Justus-Liebig-University Giessen, 35390 Giessen, Germany
8
Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
9
Inscreenex GmbH, 38124 Brunswick, Germany
*
Author to whom correspondence should be addressed.
Authors equally contributed to this work.
Academic Editor: Raj Kishore
Cells 2021, 10(6), 1326; https://doi.org/10.3390/cells10061326
Received: 22 April 2021 / Revised: 19 May 2021 / Accepted: 21 May 2021 / Published: 26 May 2021
Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able to activate macrophages. Fibroblasts also play a crucial role in cardiac remodeling arising from ischemic events, as they contribute to both inflammation and scar formation. To understand whether C0-C1f directly modulates fibroblast phenotype, we analyzed the impact of C0-C1f on a human fibroblast cell line in vitro by performing mRNA microarray screening, immunofluorescence staining, and quantitative real-time PCR. The underlying signaling pathways were investigated by KEGG analysis and determined more precisely by targeted inhibition of the potential signaling cascades in vitro. C0-C1f induced pro-inflammatory responses that might delay TGFβ-mediated myofibroblast conversion. TGFβ also counteracted C0-C1f-mediated fibroblast activation. Inhibition of TLR4 or NFκB as well as the delivery of miR-146 significantly reduced C0-C1f-mediated effects. In conclusion, C0-C1f induces inflammatory responses in human fibroblasts that are mediated via TRL4 signaling, which is decreased in the presence of TGFβ. Specific targeting of TLR4 signaling could be an innovative strategy to modulate C0-C1f-mediated inflammation. View Full-Text
Keywords: fibroblasts; inflammation; MYBPC3; C0-C1f; cMyBP-C; miRNA-146 fibroblasts; inflammation; MYBPC3; C0-C1f; cMyBP-C; miRNA-146
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MDPI and ACS Style

Yogeswaran, A.; Troidl, C.; McNamara, J.W.; Wilhelm, J.; Truschel, T.; Widmann, L.; Aslam, M.; Hamm, C.W.; Sadayappan, S.; Lipps, C. The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling. Cells 2021, 10, 1326. https://doi.org/10.3390/cells10061326

AMA Style

Yogeswaran A, Troidl C, McNamara JW, Wilhelm J, Truschel T, Widmann L, Aslam M, Hamm CW, Sadayappan S, Lipps C. The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling. Cells. 2021; 10(6):1326. https://doi.org/10.3390/cells10061326

Chicago/Turabian Style

Yogeswaran, Athiththan, Christian Troidl, James W. McNamara, Jochen Wilhelm, Theresa Truschel, Laila Widmann, Muhammad Aslam, Christian W. Hamm, Sakthivel Sadayappan, and Christoph Lipps. 2021. "The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling" Cells 10, no. 6: 1326. https://doi.org/10.3390/cells10061326

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