MicroRNA-221/222 Family Counteracts Myocardial Fibrosis in Pressure Overload-Induced Heart Failure
MicroRNA-221/222 Family Counteracts Myocardial Fibrosis in Pressure Overload-Induced Heart Failure
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DOI：
10.1161/hypertensionaha.117.10094
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发表时间：
2018-02-01
期刊：
影响因子：
8.3
通讯作者：
Schroen, Blanche
中科院分区：
文献类型：
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作者：
Verjans, Robin;Peters, Tim;Schroen, Blanche
压力超负荷引起心脏成纤维细胞活化和转分化，导致间质纤维化形成增加，随后心肌僵硬，舒张和收缩功能障碍，最终心力衰竭。更好地了解压力超负荷诱导的心脏重塑和纤维化的分子机制将对心力衰竭的治疗策略产生影响。microRNA（miRNA）-221/222家族由miR-221- 3 p和miR-222- 3 p组成，在小鼠和人类心脏病理学中受到差异调节，并与肾脏和肝脏纤维化呈负相关。我们研究了该miRNA家族在压力超负荷诱导的心脏重构中的作用。在严重纤维化和扩张性心肌病或主动脉瓣狭窄患者的心肌活检中，我们发现与匹配的非严重纤维化患者相比，miRNA-221/222水平显着较低。此外，主动脉瓣狭窄患者的miRNA-221/222水平与心肌纤维化程度和左心室僵硬度呈负相关。在小鼠AngII（血管紧张素II）介导的压力超负荷过程中抑制这两种miRNA导致纤维化增加，左心室扩张和功能障碍加重。在大鼠心脏成纤维细胞中，miRNA-221/222的抑制解除了TGF-β（转化生长因子-β）介导的促纤维化SMAD 2（母亲对decapentaplegic homolog 2）信号传导和下游基因表达，而两种miRNA的过表达减弱了TGF-β诱导的促纤维化信号传导。我们发现miRNA-221/222家族可能靶向参与TGF-β信号传导的几个基因，包括JNK 1（c-Jun N-末端激酶1）、TGF-β受体1和TGF-β受体2以及ETS-1（ETS原癌基因1）。我们的研究结果表明，与心力衰竭相关的miRNA-221/222家族下调使压力超负荷心脏中的促纤维化信号传导成为可能。
Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload-induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221-3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA-221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-beta (transforming growth factor-beta)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-beta-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-beta signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-beta receptor 1 and TGF-beta receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA-221/222 family enables profibrotic signaling in the pressure-overloaded heart.