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 miRNA-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 upon pressure overload. These alterations were macrophage-dependent, as in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild type into microRNA-155 knockout animals rescued the cardiomyocytes' hypertrophic response 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 miR-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target Suppressor of Cytokine Signaling 1 (Socs1), as 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.
Heymans, S., Corsten, M. F., Verhesen, W., Carai, P., van Leeuwen, R. E., Custers, K., Peters, T., Hazebroek, M., Stoger, L., Wijnands, E., Janssen, B. J., Creemers, E. E., Pinto, Y. M., Grimm, D., Schurmann, N., Vigorito, E., Thum, T., Stassen, F. R.
, Yin, X., ... Schroen, B. L.
(2013). Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure
(13), 1420-1432. https://doi.org/10.1161/CIRCULATIONAHA.112.001357