TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction
Rationale: Optimal outcome after myocardial infarction depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and/or excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI.
Objective: In this study, we examined the role of TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response.
Methods and Results: Following infarction, TREM-1 expression is up-regulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacologic inhibition using of a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and MCP-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20-22 per groups). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by FDG-PET imaging and conductance catheter studies (n=9-18 per groups). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients suffering from an acute MI (n=1015) and its concentration is an independent predictor of death.
Conclusions: These data suggest that TREM-1 could constitute a new therapeutic target during acute MI.
- Received November 12, 2014.
- Revision received April 2, 2015.
- Accepted April 3, 2015.