Stephane Heymans1, Maarten F Corsten, Wouter Verhesen, Paolo Carai, Rick E W van Leeuwen, Kevin Custers, Tim Peters, Mark Hazebroek, Lauran Stöger, Erwin Wijnands, Ben J Janssen, Esther E Creemers, Yigal M Pinto, Dirk Grimm, Nina Schürmann, Elena Vigorito, Thomas Thum, Frank Stassen, Xiaoke Yin, Manuel Mayr, Leon J de Windt, Esther Lutgens, Kristiaan Wouters, Menno P J de Winther, Serena Zacchigna, Mauro Giacca, Marc van Bilsen, Anna-Pia Papageorgiou, Blanche Schroen. 1. Center for Heart Failure Research, Department of Cardiology (S.H., M.F.C., W.V., P.C., R.E.W.v.L., K.C., T.P., M.H., M.v.B., A.-P.P., B.S.), Department of Molecular Genetics (L.S., M.P.J.d.W.), Department of Pathology (E.W., E.L.), Department of Pharmacology (B.J.J.), Department of Cardiology (L.J.d.W.), and Department of Internal Medicine (K.W.), Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands (S.H.); Center for Molecular and Cardiovascular Biology, Department of Cardiovascular Sciences, Leuven, Belgium (S.H., P.C., A.-P.P.); Department of Medical Biochemistry (L.S., E.L., M.P.J.d.W.) and Heart Failure Research Center (E.E.C., Y.M.P.), Academic Medical Center, Amsterdam, the Netherlands; Cluster of Excellence Cell Networks, Department of Infectious Diseases/Virology, Virus Host Interactions, Heidelberg University, Heidelberg, Germany (D.G., N.S.); Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK (E.V.); Institute for Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany (T.T.); Medical Microbiology, Maastricht University, Maastricht, the Netherlands (F.S.); King's BHF Centre, King's College London, London UK (X.Y., M.M.); Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany (E.L.); and Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy (S.Z., M.G.).
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.
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.
Authors: Leonne E Philippen; Ellen Dirkx; Jan B M Wit; Koos Burggraaf; Leon J de Windt; Paula A da Costa Martins Journal: Mol Ther Date: 2015-07-28 Impact factor: 11.454
Authors: Connie Wu; Pankaj Arora; Obiajulu Agha; Liam A Hurst; Kaitlin Allen; Daniel I Nathan; Dongjian Hu; Pawina Jiramongkolchai; J Gustav Smith; Olle Melander; Sander Trenson; Stefan P Janssens; Ibrahim Domian; Thomas J Wang; Kenneth D Bloch; Emmanuel S Buys; Donald B Bloch; Christopher Newton-Cheh Journal: Mol Cell Biol Date: 2016-06-29 Impact factor: 4.272