Altered MicroRNA Processing in Heritable Pulmonary Arterial Hypertension An Important Role for Smad-8
Altered MicroRNA Processing in Heritable Pulmonary Arterial Hypertension An Important Role for Smad-8
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DOI：
10.1164/rccm.201106-1130oc
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发表时间：
2011-12-15
影响因子：
24.7
通讯作者：
Aldred, Micheala A.
中科院分区：
文献类型：
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作者：
Drake, Kylie M.;Zygmunt, Deborah;Aldred, Micheala A.
理论基础：遗传性肺动脉高压(HPAH)主要由骨形态发生蛋白(BMP)II型受体(BMPR2)突变引起。最近发现的下游介体Smad-8(基因，SMAD9)的突变令人惊讶，因为Smad-8在规范的BMP信号中功能的丧失在很大程度上被Smad-1和Smad-5补偿。目的：确定HPAH基因突变是否干扰了非规范Smad介导的microRNA(MiR)过程。方法：检测PAH患者外植体肺组织中miR-21、miR-27A和miR-100的表达。MIR-21水平实际上降低了，这表明残留的规范信号用完或降解了现有的miR-21。BMPR2突变还导致三例中的两例失去miR诱导。HPAH细胞的增殖速度明显快于其他PAH细胞或对照组。MIR-21和miR-27A分别对PAEC和PASMC具有抑制增殖作用，BMP处理后PAEC的生长速度与miR-21倍增密切相关。Smad9的过表达纠正了miR的加工，并逆转了过度增殖的表型。结论：HPAH相关突变导致非规范miR加工的主要缺陷，而典型的BMP信号被部分维持。Smad-8在这个miR途径中是必不可少的，它的缺失没有被Smad-1和-5所补充；这可能是Smad-8的第一个非冗余角色。MiR-21和miR-27A的诱导可能是BMP诱导的生长抑制的关键成分，其缺失可能是HPAH血管细胞增殖的原因之一。
Rationale: Heritable pulmonary arterial hypertension (HPAH) is primarily caused by mutations of the bone morphogenetic protein (BMP) type-II receptor (BMPR2). Recent identification of mutations in the downstream mediator Smad-8 (gene, SMAD9) was surprising, because loss of Smad-8 function in canonical BMP signaling is largely compensated by Smad-1 and -5. We therefore hypothesized that noncanonical pathways may play an important role in PAH.Objectives: To determine whether HPAH mutations disrupt noncanonical Smad-mediated microRNA (miR) processing.Methods: Expression of miR-21, miR-27a, andmiR-100 was studied in pulmonary artery endothelial (PAEC) and pulmonary artery smooth muscle cells (PASMC) from explant lungs of patients with PAH.Measurements and Main Results: SMAD9 mutation completely abrogated miR induction, whereas canonical signaling was only reduced by one-third. miR-21 levels actually decreased, suggesting that residual canonical signaling uses up or degrades existing miR-21. BMPR2 mutations also led to loss of miR induction in two of three cases. HPAH cells proliferated faster than other PAH or controls. miR-21 and miR-27a each showed antiproliferative effects in PAEC and PASMC, and PAEC growth rate after BMP treatment correlated strongly with miR-21 fold-change. Overexpression of SMAD9 corrected miR processing and reversed the hyperproliferative phenotype.Conclusions: HPAH-associated mutations engender a primary defect in noncanonical miR processing, whereas canonical BMP signaling is partially maintained. Smad-8 is essential for this miR pathway and its loss was not complemented by Smad-1 and -5; this may represent the first nonredundant role for Smad-8. Induction of miR-21 and miR-27a maybe a critical component of BMP-induced growth suppression, loss of which likely contributes to vascular cell proliferation in HPAH.