MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension
MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension
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DOI：
10.1172/jci83361
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Lawrie, Allan
中科院分区：
文献类型：
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作者：
Rothman, Alexander M. K.;Arnold, Nadine D.;Lawrie, Allan
骨形态发生蛋白（BMP）信号传导的生长抑制作用的丧失已被证明可促进肺动脉内皮细胞功能障碍并诱导肺动脉平滑肌细胞（PASMC）增殖，导致肺动脉高压（PAH）的发展。微小RNA（miRs）通过协调调节mRNA靶点介导细胞功能的高阶调节;然而，miR表达会因疾病发展和药物治疗而改变。在这里，我们检查了未经治疗的PAH患者和实验模型，并确定了miR-140- 5 p水平的降低。抑制miR-140- 5 p可促进PASMC增殖和迁移。在PAH大鼠模型中，雾化递送miR-140-Sp模拟物可预防PAH的发展并减弱已建立的PAH的进展。网络和途径分析鉴定SMAD特异性E3泛素蛋白连接酶1（SMURF 1）为关键的miR-140-Sp靶标和BMP信号传导的调节剂。人体组织评价显示，PAH患者的SMURF 1升高。PASMC中的miR-140- 5 p模拟物或SMURF 1敲低改变了BMP信号传导，进一步支持这些因子作为BMP信号传导的调节剂。最后，Smurf 1的缺失保护了小鼠免受PAH的侵害，证明了在疾病发展中的关键作用。总之，这些研究将miR-140-Sp和SMURF 1确定为疾病病理学的关键调节因子，并作为治疗PAH的潜在治疗靶点。
Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-Sp mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-Sp target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-Sp and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.