Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle
Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle
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DOI：
10.1007/s00109-019-01817-6
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发表时间：
2019-10-01
影响因子：
4.7
通讯作者：
Hansmann, Georg
中科院分区：
文献类型：
--
作者：
Chouvarine, Philippe;Legchenko, Ekaterina;Hansmann, Georg
肺泡和心肌缺氧可能是肺动脉高压（PH）和心力衰竭的原因或后遗症。我们假设缺氧启动了右心室（RV）和左心室（LV）特定的表观遗传和转录促炎程序。我们通过qPCR阵列对小鼠RV和LV在常氧（Nx）和缺氧（Hx; 10% O-2）下的18小时、48小时和5d进行了750个mirna的表达筛选。其他验证包括对小鼠和人RV/LV以及新生大鼠心肌细胞（NRCMs）中的miRNA和促炎转录物进行单次qPCR分析。差异qpcr分析（RV中Hx vs. Nx， LV中Hx vs. Nx， Hx中RV vs. LV）鉴定出9个缺氧调节的mirna：让-7e-5p， miR-29c-3p, miR-127-3p, miR-130a-3p, miR-146b-5p, miR-197-3p, miR-214-3p， miR-223-3p和miR-451。缺氧下调miR-146b在右心室（p < 0.01），在左心室（p = 0.28）。硅比对显示miR-146b-5p序列与TRAF6的3'UTR具有显著的结合亲和力，已知TRAF6位于促炎NF-kB的上游。同样，缺氧诱导小鼠右心室和左心室的TRAF6、IL-6、CCL2（MCP-1）。用pre-miR-146b培养新生大鼠心肌细胞可导致TRAF6、IL-6和CCL2（MCP-1）的下调。TRAF6 mRNA的表达在终末期特发性肺动脉高压（PAH）患者的左室和左室也比非PAH对照组增加了3倍。我们在体内鉴定了成年小鼠心脏中缺氧调节的心室特异性miRNA表达谱。缺氧抑制miR-146b，从而抑制TRAF6，诱导促炎IL-6和CCL2（MCP-1）。这种新型缺氧诱导的miR-146b-TRAF6-IL-6/CCL2（MCP-1）轴可能驱动心脏纤维化和功能障碍，并可能导致心力衰竭。Chouvarine P, Legchenko E, Geldner J, Riehle C, Hansmann G.缺氧对心脏mirna和左心室炎症的影响。缺氧驱动心室特异性miRNA谱，调节心脏炎症。中心点miR-146b-5p下调TRAF6，已知其作用于促炎NF-kappa b的上游。中心点缺氧下调miR-146b并诱导小鼠RV和LV中的TRAF6、IL-6、CCL2 （MCP-1）。miR-146b在原代大鼠心肌细胞（pre-miR、anti-miR）和人外植心脏组织（终末期肺动脉高压）中的抑制调节作用得到证实。一个新的miR-146b-TRAF6-IL-6/CCL2（MCP-1）轴可能驱动心脏炎症、纤维化和心室功能障碍。
Alveolar and myocardial hypoxia may be causes or sequelae of pulmonary hypertension (PH) and heart failure. We hypothesized that hypoxia initiates specific epigenetic and transcriptional, pro-inflammatory programs in the right ventricle (RV) and left ventricle (LV). We performed an expression screen of 750 miRNAs by qPCR arrays in the murine RV and LV in normoxia (Nx) and hypoxia (Hx; 10% O-2 for 18 h, 48 h, and 5d). Additional validation included single qPCR analysis of miRNA and pro-inflammatory transcripts in murine and human RV/LV, and neonatal rat cardiomyocytes (NRCMs). Differential qPCR-analysis (Hx vs. Nx in RV, Hx vs. Nx in LV, and RV vs. LV in Hx) identified nine hypoxia-regulated miRNAs: let-7e-5p, miR-29c-3p, miR-127-3p, miR-130a-3p, miR-146b-5p, miR-197-3p, miR-214-3p, miR-223-3p, and miR-451. Hypoxia downregulated miR-146b in the RV (p < 0.01) and, less so, in the LV (trend; p = 0.28). In silico alignment showed significant binding affinity of miR-146b-5p sequence with the 3'UTR of TRAF6 known to be upstream of pro-inflammatory NF-kB. Consistently, hypoxia induced TRAF6, IL-6, CCL2(MCP-1) in the mouse RV and LV. Incubating neonatal rat cardiomyocytes with pre-miR-146b led to a downregulation of TRAF6, IL-6, and CCL2(MCP-1). TRAF6 mRNA expression was also increased by 3-fold in the RV and LV of end-stage idiopathic pulmonary arterial hypertension (PAH) patients vs. non-PAH controls. We identified hypoxia-regulated, ventricle-specific miRNA expression profiles in the adult mouse heart in vivo. Hypoxia suppresses miR-146b, thus de-repressing TRAF6, and inducing pro-inflammatory IL-6 and CCL2(MCP-1). This novel hypoxia-induced miR-146b-TRAF6-IL-6/CCL2(MCP-1) axis likely drives cardiac fibrosis and dysfunction, and may lead to heart failure. Key messages Chouvarine P, Legchenko E, Geldner J, Riehle C, Hansmann G. Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle. center dot Hypoxia drives ventricle-specific miRNA profiles, regulating cardiac inflammation. center dot miR-146b-5p downregulates TRAF6, known to act upstream of pro-inflammatory NF-kappa B. center dot Hypoxia downregulates miR-146b and induces TRAF6, IL-6, CCL2 (MCP-1) in the murine RV and LV. center dot The inhibitory regulatory effects of miR-146b are confirmed in primary rat cardiomyocytes (pre-miR, anti-miR) and human explant heart tissue (endstage pulmonary arterial hypertension). center dot A novel miR-146b-TRAF6-IL-6/CCL2(MCP-1) axis likely drives cardiac inflammation, fibrosis and ventricular dysfunction.