Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure

被引：236

作者：

Heymans, Stephane ^{[1
,7
,8
]}

Corsten, Maarten F. ^{[1
]}

Verhesen, Wouter ^{[1
]}

Carai, Paolo ^{[1
,8
]}

van Leeuwen, Rick E. W. ^{[1
]}

Custers, Kevin ^{[1
]}

Peters, Tim ^{[1
]}

Hazebroek, Mark ^{[1
]}

Stoeger, Lauran ^{[2
,9
]}

Wijnands, Erwin ^{[3
]}

Janssen, Ben J. ^{[4
]}

Creemers, Esther E. ^{[10
]}

Pinto, Yigal M. ^{[10
]}

Grimm, Dirk ^{[11
]}

Schuermann, Nina ^{[11
]}

Vigorito, Elena ^{[12
]}

Thum, Thomas ^{[13
]}

Stassen, Frank ^{[14
]}

Yin, Xiaoke ^{[15
]}

Mayr, Manuel ^{[15
]}

de Windt, Leon J. ^{[5
]}

Lutgens, Esther ^{[3
,9
,16
]}

Wouters, Kristiaan ^{[6
]}

de Winther, Menno P. J. ^{[2
,9
]}

Zacchigna, Serena ^{[17
]}

Giacca, Mauro ^{[17
]}

van Bilsen, Marc ^{[1
]}

Papageorgiou, Anna-Pia ^{[1
,8
]}

Schroen, Blanche ^{[1
]}

机构：

[1] Maastricht Univ, Ctr Heart Failure Res, Dept Cardiol, Maastricht, Netherlands

[2] Maastricht Univ, Dept Mol Genet, Maastricht, Netherlands

[3] Maastricht Univ, Dept Pathol, Maastricht, Netherlands

[4] Maastricht Univ, Dept Pharmacol, Maastricht, Netherlands

[5] Maastricht Univ, Dept Cardiol, Maastricht, Netherlands

[6] Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Maastricht, Netherlands

[7] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands

[8] Ctr Mol & Cardiovasc Biol, Dept Cardiovasc Sci, Louvain, Belgium

[9] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands

[10] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[11] Heidelberg Univ, Cluster Excellence Cell Networks, Dept Infect Diseases Virol Virus Host Interact, Heidelberg, Germany

[12] Babraham Inst, Lab Lymphocyte Signaling & Dev, Cambridge, England

[13] Hannover Med Sch, Inst Mol & Translat Therapeut Strategies, Hannover, Germany

[14] Maastricht Univ, Maastricht, Netherlands

[15] Kings Coll London, Kings BHF Ctr, London, England

[16] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent, Munich, Germany

[17] Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34012 Trieste, Italy

来源：

CIRCULATION | 2013年 / 128卷 / 13期

关键词：

heart failure; hypertrophy; inflammation; microRNAs; REGULATORY T-CELLS; HEART-FAILURE; PRESSURE-OVERLOAD; SIGNAL TRANSDUCER; INFLAMMATION; DYSFUNCTION; ACTIVATION; ARTHRITIS; COMPONENT; MEDIATORS;

D O I：

10.1161/CIRCULATIONAHA.112.001357

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.

引用

页码：1420 / 1432

页数：13

共 43 条

[1] Cathepsin K gene disruption does not affect murine aneurysm formation [J].