Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure

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. hypertension-induced target organ damage and hypertrophy, is a potent promoter of inflammation. 5 The signaling mechanisms that mediate these effects, however, remain largely obscure. In this study, we show that microRNA-155 (miR-155) expression by macrophages is a powerful mediator of cardiac hypertrophy and failure through the upregulation of proinflammatory paracrine signaling. Clinical Perspective on p 1432MicroRNAs are small noncoding RNAs that inhibit gene expression of complementary target genes at the posttranscriptional level. 6 Although others have studied the implication of cardiomyocyte-or fibroblast-derived microRNAs, 7-9 inflammatory microRNAs have hitherto remained unaddressed in pressure overload-induced heart disease. MiR-155 expression is upregulated in a multitude of inflammatory diseases, including rheumatoid arthritis and multiple sclerosis. MethodsAn expanded Methods section is available in the online-only Data Supplement. Animal StudiesAll mouse experiments were performed according to the local relevant guidelines; group sizes are summarized in the Table. Male miR-155 knockout (KO) and wild-type (WT) C57Bl/6J mice (10-12 weeks old) 13 were su...

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

“…These previous findings support our finding that miR‐133a is closely related to cardiac hypertrophy. The specificity of the relation between miR‐133a, CTGF, and asymmetric hypertrophy in LBBB hearts is further emphasized by the lack of local overexpression of miR‐199b and miR‐155f, which are often up‐regulated during pressure overload and concentric hypertrophy 13, 14. These results from a clinically relevant large animal model support the concept that miR‐133a plays an important role in the hypertrophic response of cardiomyocytes under conditions of increased myocardial strain.…”

“…miR‐1, miR‐133a, miR‐155f, and miR‐199b have been linked to cardiac hypertrophy,11, 12, 13, 14 while miR‐29c and miR‐30c were described in cardiac fibrosis 15, 16, 17. Furthermore, miR‐146a, miR‐146b, miR‐222, and miR‐499 were included in the analysis 18.…”

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…A famous study showed that miR‐155 expression in macrophages promoted cardiac inflammation, hypertrophy, and failure in response to pressure overload. And these effects were, at least partly, mediated by the direct miR‐155 target, suppressor of cytokine signaling 1 21. Another important finding of this study is that the BRCA1‐signaling pathway is involved in the regulation of expression of miR‐155 in cardiac hypertrophy.…”

“…In a previous study, we elucidated the feasibility of using our constructed miRNA reporter imaging system to monitor the location and magnitude of expression levels of miR‐22 in cardiac hypertrophy in vitro and in vivo 19. Most recently, miR‐155 was reported to be expressed in atherosclerotic plaques and proinflammatory macrophages and the in vivo function of miR‐155 in cardiomyocyte hypertrophy was also manifested 20, 21, 22. Another excellent study in this research area by Shyam's group demonstrated a previously unknown role for BRCA1 in epigenetic control of miR‐155 23…”

MicroRNA-155 in the Heart

“…12 Although the authors did not fully explore the mechanisms that directly control miR-155 expression, they did find that the relative levels of expression of miR-155 in bone marrowderived macrophages are much greater than that of ECs, suggesting that miR-155 expression in monocytes/macrophages may have a greater influence over miR-155 function in vivo. Interestingly, a recent report by Heymans et al 13 showed that miR-155 in macrophages drives the inflammatory response to pressure overload in the myocardium, where the absence of proinflammatory miR-155 protects from cardiac hypertrophy and heart failure. Thus, although miR-155 may antagonize angiogenesis in ECs, the expression of miR-155 in macrophages overpowers any EC-driven inhibitory effects on angiogenesis, and hence, macrophage-driven mechanisms dominate in vivo.…”