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Eur Heart J. 2015 Jun 14;36(23):1478-88. doi: 10.1093/eurheartj/ehu225. Epub 2014 Jun 20.

Silencing of CCR2 in myocarditis.

Author information

1
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany mnahrendorf@mgh.harvard.edu florian.leuschner@med.uni-heidelberg.de.
2
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
3
Alnylam Pharmaceuticals, 300 3rd Street, Cambridge, MA 02142, USA.
4
Department of Chemical Engineering, Massachusetts Institute of Technology, University Hospital Heidelberg, Heidelberg, Germany.
5
Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
6
Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg 69120, Germany.
7
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
8
Department of Chemical Engineering, Massachusetts Institute of Technology, University Hospital Heidelberg, Heidelberg, Germany David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA Division of Health Science Technology, Massachusetts Institute of Technology, Boston, MA, USA Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Boston, MA, USA.
9
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
10
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA mnahrendorf@mgh.harvard.edu florian.leuschner@med.uni-heidelberg.de.

Abstract

BACKGROUND:

Myocarditis is characterized by inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function. Monocytes are the most prominent population of accumulating leucocytes. We investigated whether in vivo administration of nanoparticle-encapsulated siRNA targeting chemokine (C-C motif) receptor 2 (CCR2)-a chemokine receptor crucial for leucocyte migration in humans and mice--reduces inflammation in autoimmune myocarditis.

METHODS AND RESULTS:

In myocardium of patients with myocarditis, CCL2 mRNA levels and CCR2(+) cells increased (P < 0.05), motivating us to pursue CCR2 silencing. Flow cytometric analysis showed that siRNA silencing of CCR2 (siCCR2) reduced the number of Ly6C(high) monocytes in hearts of mice with acute autoimmune myocarditis by 69% (P < 0.05), corroborated by histological assessment. The nanoparticle-delivered siRNA was not only active in monocytes but also in bone marrow haematopoietic progenitor cells. Treatment with siCCR2 reduced the migration of bone marrow granulocyte macrophage progenitors into the blood. Cellular magnetic resonance imaging (MRI) after injection of macrophage-avid magnetic nanoparticles detected myocarditis and therapeutic effects of RNAi non-invasively. Mice with acute myocarditis showed enhanced macrophage MRI contrast, which was prevented by siCCR2 (P < 0.05). Follow-up MRI volumetry revealed that siCCR2 treatment improved ejection fraction (P < 0.05 vs. control siRNA-treated mice).

CONCLUSION:

This study highlights the importance of CCR2 in the pathogenesis of myocarditis. In addition, we show that siCCR2 affects leucocyte progenitor trafficking. The data also point to a novel therapeutic strategy for the treatment of myocarditis.

KEYWORDS:

Inflammation; Molecular imaging; Myocarditis; Nanoparticle; siRNA

PMID:
24950695
PMCID:
PMC4465633
DOI:
10.1093/eurheartj/ehu225
[Indexed for MEDLINE]
Free PMC Article

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