N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro.
Myocardial infarction (MI) leads to loss and degradation of contractile cardiac tissue followed by sterile inflammation of the myocardium through activation and recruitment of innate and adaptive cells of the immune system. Recently, it was shown that cardiac myosin binding protein-C (cMyBP-C), a protein of the cardiac sarcomere, is degraded following MI, releasing a predominant N-terminal 40-kDa fragment (C0C1f) into myocardial tissue and the systemic circulation. We hypothesized that early release of C0C1f contributes to the initiation of inflammation and plays a key role in recruitment and activation of immune cells. Therefore, we investigated the role of C0C1f on macrophage/monocyte activation using both mouse bone marrow-derived macrophages and human monocytes. Here we demonstrate that C0C1f leads to macrophage/monocyte activation in vitro. Furthermore, C0C1f induces strong upregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and interleukin-1β (IL-1β)) in cultured murine macrophages and human monocytes, resulting in a pro-inflammatory phenotype. We identified the toll-like receptor 4 (TLR4), toll-like receptor 2 (TLR2), and Advanced Glycosylation End Product-Specific Receptor (RAGE) as potential receptors for C0C1f whose activation leads to mobilization of the NFκB signaling pathway, a central mediator of the pro-inflammatory signaling cascade. Thus, C0C1f appears to be a key player in the initiation of inflammatory processes and might also play an important role upon MI.
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany.
Christoph
C
Lipps
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany.
Jenine H
JH
Nguyen
Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Lukas
L
Pyttel
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
Thomas L
TL
Lynch
Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Christoph
C
Liebetrau
Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Ganna
G
Aleshcheva
Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Sandra
S
Voss
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany.
Oliver
O
Dörr
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany.
Holger M
HM
Nef
Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Helge
H
Möllmann
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany; Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany.
Christian W
CW
Hamm
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
Sakthivel
S
Sadayappan
Department of Experimental Cardiology, Medical Clinics I, Justus Liebig University, 35392 Giessen, Germany; Kerckhoff Heart and Thorax Center, 61231 Bad Nauheim, Germany. Electronic address: christian.troidl@innere.med.uni-giessen.de.
Christian
C
Troidl
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000099163:Myosin Binding Protein C
C0C1f; Cardiac myosin binding protein-C; Cell signaling/signal transduction; Inflammation; Ischemic biology - basic studies; Myocardial infarction