AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension
AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension
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DOI：
10.1093/eurheartj/ehs060
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发表时间：
2014-12-01
影响因子：
39.3
通讯作者：
Huber, Lars C.
中科院分区：
文献类型：
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作者：
Brock, Matthias;Samillan, Victor J.;Huber, Lars C.
骨形态发生蛋白受体2（BMPR 2）的失调是几种形式的肺动脉高压的标志性特征。我们最近在一个高度保守的通路中鉴定了microRNA miR-20 a作为BMPR 2表达的调节因子。为了解决这一途径在体内的病理生理学相关性，我们采用miR-20 a和研究是否特异性抑制miR-20 a可以恢复BMPR 2的功能水平，反过来，可能会阻止肺动脉血管remodeling.Methods和结果对于特异性抑制miR-20 a，合成胆固醇修饰的RNA寡核苷酸（miR-20 a）。通过使用低氧诱导的肺动脉高压小鼠模型进行小鼠实验，并分析动物组织的右心室肥大和肺动脉血管重塑。用EschomiR-20 a处理增强了肺组织中BMPR 2的表达水平;此外，EschomiR-20 a显著降低了小肺动脉的壁厚度和管腔闭塞，并降低了右心室肥大。为了评估BMPR 2信号传导和增殖，我们用人肺动脉平滑肌细胞（HPASMCs）进行了体外实验。用HpasomiR-20 a转染HPASMC导致BMPR 2下游靶标的活化，显示Id-1和Id-2的活化增加。结论miR-20 a可特异性靶向作用于肺动脉高压模型，并能抑制肺动脉高压大鼠肺动脉平滑肌细胞的增殖。我们的数据强调，用BMPR 20 a治疗恢复了肺动脉中BMPR 2的功能水平，并防止了血管重塑的发展。
Aims Dysregulation of the bone morphogenetic protein receptor type 2 (BMPR2) is a hallmark feature that has been described in several forms of pulmonary hypertension. We recently identified the microRNA miR-20a within a highly conserved pathway as a regulator of the expression of BMPR2. To address the pathophysiological relevance of this pathway in vivo, we employed antagomiR-20a and investigated whether specific inhibition of miR-20a could restore functional levels of BMPR2 and, in turn, might prevent pulmonary arterial vascular remodelling.Methods and results For specific inhibition of miR-20a, cholesterol-modified RNA oligonucleotides (antagomiR-20a) were synthesized. The experiments in mice were performed by using the hypoxia-induced mouse model for pulmonary hypertension and animal tissues were analysed for right ventricular hypertrophy and pulmonary arterial vascular remodelling. Treatment with antagomiR-20a enhanced the expression levels of BMPR2 in lung tissues; moreover, antagomiR-20a significantly reduced wall thickness and luminal occlusion of small pulmonary arteries and reduced right ventricular hypertrophy. To assess BMPR2 signalling and proliferation, we performed in vitro experiments with human pulmonary arterial smooth muscle cells (HPASMCs). Transfection of HPASMCs with antagomiR-20a resulted in activation of downstream targets of BMPR2 showing increased activation of Id-1 and Id-2. Proliferation of HPASMCs was found to be reduced upon transfection with antagomiR-20a.Conclusion This is the first report showing that miR-20a can be specifically targeted in an in vivo model for pulmonary hypertension. Our data emphasize that treatment with antagomiR-20a restores functional levels of BMPR2 in pulmonary arteries and prevents the development of vascular remodelling.