MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18.
MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18.
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DOI：
10.1016/j.xcrm.2022.100871
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发表时间：
2022-12-20
影响因子：
14.3
通讯作者：
Marban, Eduardo
中科院分区：
文献类型：
--
作者：
Sanchez, Lizbeth;Mesquita, Thassio;Zhang, Rui;Liao, Ke;Rogers, Russell;Lin, Yen-Nien;Miguel-dos-Santos, Rodrigo;Akhmerov, Akbarshakh;Li, Liang;Nawaz, Asma;Holm, Kevin;Marban, Eduardo
具有选择性改变的核苷酸的化学修饰的mRNA（CMmRNA）用于递送转基因，但翻译效率是可变的。我们将编码人T-box转录因子18（CMmTBX 18）的CMmRNA转染到房室传导阻滞大鼠的心脏细胞或左心室中。来自CMmTBX 18的TBX 18蛋白表达是微弱且短暂的，但Argonaute 2抑制剂Acriflavine可提高TBX 18水平。小RNA测序鉴定了CMmTBX 18转染细胞中两种上调的microRNA（miR）。miR-1- 3 p和miR-1b拮抗剂miR与CMmTBX 18的联合给药延长了TBX 18在体外和体内的表达，并且足以产生能够起搏心脏的电刺激。不同的抑制性miR同样限制VEGF-A CMmRNA的表达。因此，细胞通过上调抑制性miR来抵抗CMmRNA治疗性转基因的翻译。抑制性miR的阻断增强驱动生物起搏或血管生成的基因的CMmRNA表达。这种对抗策略构成了提高CMmRNA疗法的功效和效率的方法。内源性microRNA抑制化学修饰的mRNA翻译阻断抑制性microRNA增强转基因表达和生物活性TBX 18的持续翻译导致生物起搏活性Sanchez et al.显示编码人TBX 18的化学修饰的mRNA在体外和体内被microRNA抑制。阻断抑制性microRNA功能的对策导致了强大的TBX 18蛋白表达和模拟房室传导阻滞大鼠模型中起搏细胞的电刺激的产生。
Chemically modified mRNA (CMmRNA) with selectively altered nucleotides are used to deliver transgenes, but translation efficiency is variable. We have transfected CMmRNA encoding human T-box transcription factor 18 (CMmTBX18) into heart cells or the left ventricle of rats with atrioventricular block. TBX18 protein expression from CMmTBX18 is weak and transient, but Acriflavine, an Argonaute 2 inhibitor, boosts TBX18 levels. Small RNA sequencing identified two upregulated microRNAs (miRs) in CMmTBX18-transfected cells. Co-administration of miR-1-3p and miR-1b antagomiRs with CMmTBX18 prolongs TBX18 expression in vitro and in vivo and is sufficient to generate electrical stimuli capable of pacing the heart. Different suppressive miRs likewise limit the expression of VEGF-A CMmRNA. Cells therefore resist translation of CMmRNA therapeutic transgenes by upregulating suppressive miRs. Blockade of suppressive miRs enhances CMmRNA expression of genes driving biological pacing or angiogenesis. Such counterstrategies constitute an approach to boost the efficacy and efficiency of CMmRNA therapies. Chemically modified mRNA translation is suppressed by endogenous microRNAs Blockade of suppressive microRNAs enhance transgene expression and biological activity Sustained translation of TBX18 results in biological pacing activity Sanchez et al. show that a chemically modified mRNA encoding human TBX18 is suppressed by microRNAs in vitro and in vivo. Counterstrategies that block suppressive microRNA function led to robust TBX18 protein expression and the generation of electrical stimuli that mimic pacemaker cells in a rat model of atrioventricular block.
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影响因子：
46.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Kogut I;McCarthy SM;Pavlova M;Astling DP;Chen X;Jakimenko A;Jones KL;Getahun A;Cambier JC;Pasmooij AMG;Jonkman MF;Roop DR;Bilousova G
通讯作者：
Bilousova G
影响因子：
64.8
作者：
DIFRANCESCO, D
通讯作者：
DIFRANCESCO, D
影响因子：
20.1
作者：
Cho HC;Marbán E
通讯作者：
Marbán E
影响因子：
37.8
作者：
Cho JH;Zhang R;Kilfoil PJ;Gallet R;de Couto G;Bresee C;Goldhaber JI;Marbán E;Cingolani E
通讯作者：
Cingolani E