N-terminal fragment of cardiac myosin binding protein-C triggers pro-inflammatory responses in vitro

作者：Lipps Christoph; Nguyen Jenine H; Pyttel Lukas; Lynch Thomas L; Liebetrau Christoph; Aleshcheva Ganna; Voss Sandra; Doerr Oliver; Nef Holger M; Moellmann Helge; Hamm Christian W; Sadayappan Sakthivel; Troidl Christian^*

来源：Journal of Molecular and Cellular Cardiology, 2016, 99: 47-56.

DOI：10.1016/j.yjmcc.2016.09.003

• Cardiac myosin binding protein-C
• C0C1f
• Myocardial infarction
• Inflammation
• Cell signaling/signal transduction
• lschemic biology - basic studies

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 alpha (TNF alpha), and interleukin-1 beta (1L-1 beta)) 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 NF kappa B 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.

• 出版日期2016-10