A Role for miR-145 in Pulmonary Arterial Hypertension Evidence From Mouse Models and Patient Samples
A Role for miR-145 in Pulmonary Arterial Hypertension Evidence From Mouse Models and Patient Samples
复制标题
DOI：
10.1161/circresaha.112.267591
复制
发表时间：
2012-07-20
影响因子：
20.1
通讯作者：
Baker, Andrew H.
中科院分区：
文献类型：
--
作者：
Caruso, Paola;Dempsie, Yvonne;Baker, Andrew H.
原理：尽管对潜在遗传学的理解有所提高，但肺动脉高压（PAH）仍然是一种严重疾病。PAH的特征是小肺动脉的广泛重塑，包括肺动脉平滑肌细胞（PASMC）的增殖。目的：探讨miR-145在肺动脉高压（PAH）中的作用。使用定量PCR，我们证明了暴露于缺氧的野生型小鼠中miR-145的表达增加。通过测量右心室收缩压、右心室肥大和重塑肺动脉百分比，在miR-145敲除小鼠和抗miR治疗小鼠中评估PAH。miR-145缺乏和抗miR介导的减少可显著防止PAH的发生。相比之下，miR-143反式miR没有影响。此外，与未受影响的对照受试者相比，我们观察到特发性和遗传性PAH患者肺组织中miR-145的上调，并证明了miR-145在此类患者重塑血管的SMC中的表达。最后，我们发现，在BMPR 2突变患者培养的原代PASMCs和BMPR 2缺陷小鼠的肺中，miR-145表达水平升高。miR-145的下调可防止PAH的发生。在遗传性PAH和特发性PAH患者样本中，miR-145在重塑血管中表达，BMPR 2突变导致小鼠和PAH患者中miR-145上调。调控miR-145可能是PAH治疗的一种新策略。(Circ Res. 2012;111：290-300）。
Rationale: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling.Objective: We assessed the role of miR-145 in PAH.Methods and Results: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice.Conclusions: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment. (Circ Res. 2012;111:290-300.)