253Absence of microRNA-155 protects against adverse cardiac inflammation and hypertrophy during pressure overload and prevents heart failure

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While neurohumoral and myocyte signalling represent the main focus as underlying mechanisms behind cardiac remodeling and subsequent heart failure, the implication of the inflammatory system is increasingly gaining interest. In the current study, we show that the pro-inflammatory microRNA-155 (miR-155) functions selectively in cardiac macrophages and impacts cardiac structure and function during pressure overload.

We subjected miR-155 KO and WT mice to pressure overload by angiotensin II (AngII) infusion and transverse aortic constriction (TAC) to induce cardiac hypertrophy, inflammation and failure. Whereas AngII and TAC significantly increased both cardiac mass and hypertrophic signalling in WT mice, the absence of miR-155 inhibited this hypertrophic response. Moreover, absence of miR-155 prevented macrophage influx in the heart following pressure overload. These data were confirmed with antagomiRs against miR-155 in AngII-treated mice.

In situ hybridization identified cardiac miR-155 in macrophages whereas very little miR-155 was detected in cardiac myocytes. Bone marrow transplantations with miR-155 KO and WT mice and in vitro experiments subjecting cardiac myocytes to the miR-155 KO macrophage secretome independently showed that macrophage miR-155 mediates pro-hypertrophic signalling towards cardiac myocytes. Proteomics analysis of the miR-155 KO macrophage secretome confirmed that the function of these cells is compromised, as exemplified by the reduced secretion of proteins crucial for macrophage activation and tissue infiltration including the macrophage receptor mac1, the adhesion-mediating integrins LFA1 and VLA4a, and the inflammatory cytokines IL6, TNFa, IL1B and IL12.

A macrophage miR-155 target gene that potentially mediates these effects is Suppressor of Cytokine Signalling 1 (SOCS1). In vitro SOCS1-rescue re-established the capacity of the miR-155 KO macrophage secretome to induce cardiac myocyte hypertrophy. Finally, we found the activation of the hypertrophic and inflammatory Signal Transducer and Activator of Transcription 3 (STAT3) to be blunted in miR-155 KO pressure overloaded hearts and macrophages, and in cardiac myocytes subjected to the miR-155 KO macrophage secretome.

In conclusion, we have identified miR-155 as a crucial regulator of cardiac inflammation, hypertrophy and failure, by its central role in macrophage function. These findings reveal that microRNAs can contribute to myocardial disease via cardiac macrophages, demonstrate the causative relation between inflammatory signalling and heart failure, and implicate miR-155 as a therapeutic disease target in heart failure.

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