Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure
Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure
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DOI：
10.1161/circulationaha.112.001357
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发表时间：
2013-09-24
期刊：
影响因子：
37.8
通讯作者：
Schroen, Blanche
中科院分区：
文献类型：
--
作者：
Heymans, Stephane;Corsten, Maarten F.;Schroen, Blanche
背景慢性高血压引起的心脏肥厚和随后的心力衰竭是心血管研究的主要挑战。除了神经激素和心肌细胞信号通路外，越来越多的证据表明炎症信号通路在这一过程中是具有治疗靶向性的贡献者。我们最近报道，microRNA-155是感染性心肌炎心脏炎症和损伤的关键介质。方法和结果小鼠白细胞表达的microRNA-155基因缺失或药物抑制可显著减少压力超负荷所致的心脏炎症、肥大和功能障碍。这些改变依赖于巨噬细胞，因为在体内，心肌细胞特异性的microRNA-155操作不会影响心肌肥大或功能障碍，而从野生型小鼠的骨髓移植到microRNA-155基因敲除的动物中，可以挽救心肌细胞的肥大反应，反之亦然。在体外，来自microRNA-155基因敲除的巨噬细胞的培养液阻断了刺激的心肌细胞的肥大生长，证实巨噬细胞以依赖microRNA-155的旁分泌方式影响心肌细胞的生长。这些效应至少部分是由microRNA-155直接靶向细胞因子信号转导抑制因子1(SOCS1)介导的，因为在microRNA-155基因敲除的巨噬细胞中，SOCS1基因敲除后，巨噬细胞的肥大刺激能力基本恢复。结论我们的研究结果表明，MicroRNA-155在巨噬细胞中的表达促进了心脏炎症、肥大和对压力超负荷反应的衰竭。这些数据支持炎症信号在肥厚性心脏病中的致病意义，并证明了治疗性microRNA靶向治疗心力衰竭炎症的可行性。
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.