MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4.
MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4.
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DOI：
10.1161/circheartfailure.121.008686
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发表时间：
2022-04
期刊：
影响因子：
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通讯作者：
Kim IM
中科院分区：
文献类型：
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作者：
Aonuma T;Moukette B;Kawaguchi S;Barupala NP;Sepúlveda MN;Frick K;Tang Y;Guglin M;Raman SV;Cai C;Liangpunsakul S;Nakagawa S;Kim IM
MicroRNA-150(miR-150)在心力衰竭(HF)中起保护作用。长非编码RNA(NcRNA)、心肌梗死相关转录本(MIAT)在体外通过直接相互作用调节miR-150的功能。在miR-150下调的同时，MIAT在衰竭的心脏中上调，MIAT的功能获得单核苷酸多态与人类心肌梗死的风险增加相关。尽管MIAT和miR-150在心力衰竭中有相关性，但它们在体内的功能关系尚未建立，这两个ncRNAs调节心脏保护的分子机制仍然不清楚。我们使用MIAT基因敲除(KO)、同源盒A4(Hoxa4)KO、MIAT转基因(Tg)和miR-150 Tg小鼠。我们还建立了高表达MIAT和miR-150的双转基因(DTG)小鼠。然后，我们利用小鼠心肌梗死模型，通过超声心动图、免疫组织化学、转录组图谱、Western blotting和定量实时RT-PCR对心脏功能、结构和机制进行研究。此外，我们还对心力衰竭患者的心脏进行了表达分析。最后，我们使用原代成人CFs研究心脏成纤维细胞(CF)的激活，并通过体外实验确定保守的MIAT/miR-150/HOXA4轴。利用新的小鼠模型，我们证明了MIAT的基因过表达加剧了心脏重构，而MIAT的基因缺失则保护心脏免受心肌梗死的影响。重要的是，miR-150的过度表达可以减弱MIAT引起的心肌梗死后的有害影响。对MIAT缺失的小鼠心脏进行的全基因组转录分析表明，Hoxa4是MIAT/miR-150轴的一个新的下游靶点。从缺血心肌分离的CFs在缺氧/复氧条件下Hoxa4表达上调。HOXA4在心力衰竭患者中也表达上调。此外，小鼠缺乏Hoxa4可以保护心脏免受心肌梗死的影响。最后，CFmiR-150的保护作用部分归因于对促纤维化Hoxa4的直接和功能性抑制。我们的发现描述了MIAT、miR-150和Hoxa4之间的关键功能相互作用是与缺血性心力衰竭相关的一种新的调控机制。
MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA (ncRNA), Myocardial Infarction-Associated Transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single nucleotide polymorphisms in MIAT are associated with increased risk of MI in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these two ncRNAs regulate cardiac protection remain elusive. We use MIAT knockout (KO), homeobox a4 (Hoxa4) KO, MIAT transgenic (TG) and miR-150 TG mice. We also develop double transgenic (DTG) mice overexpressing MIAT and miR-150. We then employ a mouse model of MI followed by cardiac functional, structural and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting and quantitative real-time RT-PCR. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast (CF) activation using primary adult human CFs and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in CFs isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of CF miR-150 are partially attributed to the direct and functional repression of pro-fibrotic Hoxa4. Our findings delineate a pivotal functional interaction among MIAT, miR-150 and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.