Silencing of CCR2 in myocarditis

被引：116

作者：

Leuschner, Florian ^{[1
,2
,3
,4
]}

Courties, Gabriel ^{[1
,2
]}

Dutta, Partha ^{[1
,2
]}

Mortensen, Luke J. ^{[1
,2
]}

Gorbatov, Rostic ^{[1
,2
]}

Sena, Brena ^{[1
,2
]}

Novobrantseva, Tatiana I. ^{[5
]}

Borodovsky, Anna ^{[5
]}

Fitzgerald, Kevin ^{[5
]}

Koteliansky, Victor ^{[6
]}

Iwamoto, Yoshiko ^{[1
,2
]}

Bohlender, Marina ^{[3
,4
]}

Meyer, Soeren ^{[3
,4
]}

Lasitschka, Felix ^{[7
]}

Meder, Benjamin ^{[3
,4
]}

Katus, Hugo A. ^{[3
,4
]}

Lin, Charles ^{[1
,2
]}

Libby, Peter ^{[8
]}

Swirski, Filip K. ^{[1
,2
]}

Anderson, Daniel G. ^{[6
,9
,10
,11
]}

Weissleder, Ralph ^{[1
,2
,12
]}

Nahrendorf, Matthias ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Boston, MA 02114 USA

[3] Med Univ Hosp Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany

[4] DZHK German Ctr Cardiovasc Res, Heidelberg, Germany

[5] Alnylam Pharmaceut, Cambridge, MA 02142 USA

[6] Univ Heidelberg Hosp, Massachusetts Inst Technol, Dept Chem Engn, D-69120 Heidelberg, Germany

[7] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany

[8] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA

[9] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[10] MIT, Div Hlth Sci Technol, Cambridge, MA 02139 USA

[11] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[12] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA

来源：

EUROPEAN HEART JOURNAL | 2015年 / 36卷 / 23期

关键词：

Inflammation; Myocarditis; Molecular imaging; siRNA; Nanoparticle; MONOCYTE CHEMOATTRACTANT PROTEIN-1; CARDIOVASCULAR MAGNETIC-RESONANCE; LIPID-LIKE MATERIALS; CARDIAC TROPONIN-I; AUTOIMMUNE MYOCARDITIS; ENDOMYOCARDIAL BIOPSY; SPLENIC RESERVOIR; EUROPEAN-SOCIETY; PROGENITOR CELLS; IRON-OXIDE;

D O I：

10.1093/eurheartj/ehu225

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1478 / U41

页数：12

共 41 条

[41] Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach [J].

Yilmaz, Ali ;

Dengler, Michael A. ;

van der Kuip, Heiko ;

Yildiz, Handan ;

Roesch, Sabine ;

Klumpp, Siegfried ;

Klingel, Karin ;

Kandolf, Reinhard ;

Helluy, Xavier ;

Hiller, Karl-Heinz ;

Jakob, Peter M. ;

Sechtem, Udo .

EUROPEAN HEART JOURNAL, 2013, 34 (06) :462-475

← 1 2 3 4 5 →