1. Macrophage microRNA-155 promotes cardiac hypertrophy and failure
- Author
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Yigal M. Pinto, Paolo Carai, Wouter Verhesen, Rick van Leeuwen, Anna-Pia Papageorgiou, Ben J. A. Janssen, Kevin Custers, Blanche Schroen, Dirk Grimm, Marc van Bilsen, Esther E. Creemers, Lauran J. Stöger, Xiaoke Yin, Erwin Wijnands, Serena Zacchigna, Manuel Mayr, Menno P.J. de Winther, Leon J. De Windt, Stephane Heymans, Mark R. Hazebroek, Elena Vigorito, Mauro Giacca, Tim Peters, Maarten F. Corsten, Esther Lutgens, Thomas Thum, Nina Schürmann, Kristiaan Wouters, Frank R. M. Stassen, S., Heyman, M. F., Corsten, W., Verhesen, P., Carai, R. E., W, K., Custer, T., Peter, M., Hazebroek, L., Stöger, E., Wijnand, B. J., Janssen, E. E., Creemer, Y. M., Pinto, D., Grimm, N., Schürmann, E., Vigorito, T., Thum, F., Stassen, X., Yin, M., Mayr, L. J., De, E., Lutgen, K., Wouter, M. P., J, Zacchigna, Serena, Giacca, Mauro, M. v., Bilsen, A., Papageorgiou, B., Schroen, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, AII - Amsterdam institute for Infection and Immunity, Medical Biochemistry, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Pathologie, Farmacologie en Toxicologie, Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Fysiologie, and Cardiologie
- Subjects
Male ,Heart disease ,genetics, Myocyte ,030204 cardiovascular system & hematology ,Inbred C57BL ,Muscle hypertrophy ,Mice ,0302 clinical medicine ,genetics ,Myocytes, Cardiac ,Cells, Cultured ,Mice, Knockout ,0303 health sciences ,Cultured ,Hypertensive heart disease ,3. Good health ,metabolism/pathology, Rats ,Cultured, Heart Failure ,Inbred C57BL, Mice ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Cardiac ,genetics/pathology, Humans, Inflammation ,metabolism/pathology ,Myocarditis ,Cells ,Knockout ,Inflammation ,Animals, Cardiomegaly ,genetics/pathology, Cells ,genetics/pathology, Macrophages ,metabolism/pathology, Male, Mice, Mice ,Knockout, MicroRNAs ,genetics, Myocytes ,Cardiomegaly ,genetics/pathology, Cell ,03 medical and health sciences ,Physiology (medical) ,medicine ,Animals ,Humans ,Knockout, MicroRNA ,030304 developmental biology ,Pressure overload ,Heart Failure ,Myocytes ,business.industry ,Suppressor of cytokine signaling 1 ,Macrophages ,genetics/pathology ,medicine.disease ,Rats ,Mice, Inbred C57BL ,MicroRNAs ,Heart failure ,Immunology ,Cancer research ,business ,genetics/pathology, Macrophage - Abstract
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.
- Published
- 2013