H19 Induces Abdominal Aortic Aneurysm Development and Progression.
H19 Induces Abdominal Aortic Aneurysm Development and Progression.
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DOI：
10.1161/circulationaha.117.032184
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发表时间：
2018-10-09
期刊：
影响因子：
37.8
通讯作者：
Maegdefessel L
中科院分区：
文献类型：
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作者：
Li DY;Busch A;Jin H;Chernogubova E;Pelisek J;Karlsson J;Sennblad B;Liu S;Lao S;Hofmann P;Bäcklund A;Eken SM;Roy J;Eriksson P;Dacken B;Ramanujam D;Dueck A;Engelhardt S;Boon RA;Eckstein HH;Spin JM;Tsao PS;Maegdefessel L
长非编码RNA(LncRNAs)已成为多种生物过程和疾病中的重要分子调控因子。在这里，我们试图确定和功能特征的lncRNAs作为腹主动脉瘤(AAA)发展的潜在介质。我们研究了ApoE−/−小鼠(n=8)血管紧张素II(AngII)注射和C57BL/6野生型小鼠(n=12)猪胰腺弹性酶(PPE)注射两种小鼠AAA模型的RNA转录表达。与假手术对照组相比，lncRNAH19被确定为在两种小鼠动脉瘤模型中上调程度最高的转录本之一。QRT-PCR和原位杂交证实了这一点。利用体内定位的反义寡核苷酸(LNA-GapmeRs)，实验性地击倒H19，显著限制了两种模型中的动脉瘤生长。进展性动脉瘤中H19表达上调与SMC含量及SMC凋亡相关。重要的是，可以在人类腹主动脉瘤组织样本中观察到类似的模式，并在一种新的临床前LDLR−/−尤卡坦小型猪动脉瘤模型中观察到类似的模式。在体外，H19基因的敲除可显著降低培养的人主动脉平滑肌细胞的凋亡率，而H19基因的过表达则具有相反的作用。值得注意的是，H19依赖的SMC凋亡机制似乎独立于嵌入H19基因第一外显子的miR-675。一个定制的转录因子阵列确定低氧诱导因子1-α(HIF1α)是主要的下游效应因子。H19和HIF1α之间的胞质相互作用和P53的稳定与SMC凋亡率的增加有关。此外，H19通过将转录因子特异性蛋白1(Sp1)招募到启动子区域来诱导HIF1α的转录。LncRNAH19是AAA发生发展过程中SMC存活的一个新的调节因子。抑制H19的表达可能成为治疗主动脉瘤疾病的一个新的分子靶点。
Long noncoding RNAs (lncRNAs) have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize lncRNAs as potential mediators in abdominal aortic aneurysm (AAA) development. We profiled RNA transcript expression in two murine AAA models, Angiotensin II (ANGII) infusion in ApoE−/− mice (n=8) and porcine pancreatic elastase (PPE) instillation in C57BL/6 wildtype mice (n=12). The lncRNA H19 was identified as one of the most highly up-regulated transcripts in both mouse aneurysm models compared to sham-operated controls. This was confirmed by qRT-PCR and in situ hybridization. Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human AAA tissue samples, and in a novel preclinical LDLR−/− Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, while overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1-alpha (HIF1α) as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and HIF1α and sequential p53 stabilization. Additionally, H19 induced transcription of HIF1α via recruiting the transcription factor specificity protein 1 (Sp1) to the promoter region. The lncRNA H19 is a novel regulator of SMC survival in AAA development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.