Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness.
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DOI：
10.1371/journal.pone.0082308
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Swärd K
中科院分区：
文献类型：
--
作者：
Ekman M;Bhattachariya A;Dahan D;Uvelius B;Albinsson S;Swärd K
最近的工作已经揭示了microRNA（miRNA）miR-29在细胞外基质重塑中的作用。部分膀胱出口梗阻是前列腺肥大老年男性的常见疾病，导致下尿路基质合成并增加膀胱硬度。在这里，我们测试了这样的假设，即miR-29在出口梗阻的膀胱中被抑制，并且这对蛋白质合成和基质重塑有影响，导致膀胱硬度增加。c-Myc、NF-κB和SMAD 3均抑制miR-29，在部分膀胱出口梗阻后大鼠逼尿肌中被激活，但时间不同。c-Myc和NF-κB活化在梗阻后早期发生，SMAD 3磷酸化在梗阻后较晚时增加，6周时显著升高。c-Myc、NF-κB和SMAD 3激活分别与梗阻10天时miR-29 B和miR-29 c的抑制相关，与6周时miR-29 c的抑制相关。mRNA微阵列分析显示，出口阻塞后miR-29的减少与miR-29靶mRNA水平的增加相关，包括原弹性蛋白、基质细胞蛋白Sparc和胶原IV的mRNA。出口阻塞增加了八个检查的miR-29靶点中的八个的蛋白水平，包括原弹性蛋白和Sparc。用antimiR-29 c和miR-29 c模拟物转染人膀胱平滑肌细胞引起体外靶蛋白水平的相互变化。在小鼠中，他莫昔芬诱导的和平滑肌特异性的Dicer缺失降低了miR-29的表达，增加了原弹性蛋白和膀胱平滑肌细胞周围基底层的厚度。它也增加了逼尿肌僵硬独立出口梗阻。综上所述，我们的研究支持了一个模型，其中c-Myc、NF-κB和SMAD 3的联合抑制作用减少了膀胱出口梗阻中的miR-29，并且其中所导致的miR-29的下降有助于基质重塑和逼尿肌被动机械特性的改变。
Recent work has uncovered a role of the microRNA (miRNA) miR-29 in remodeling of the extracellular matrix. Partial bladder outlet obstruction is a prevalent condition in older men with prostate enlargement that leads to matrix synthesis in the lower urinary tract and increases bladder stiffness. Here we tested the hypothesis that miR-29 is repressed in the bladder in outlet obstruction and that this has an impact on protein synthesis and matrix remodeling leading to increased bladder stiffness. c-Myc, NF-κB and SMAD3, all of which repress miR-29, were activated in the rat detrusor following partial bladder outlet obstruction but at different times. c-Myc and NF-κB activation occurred early after obstruction, and SMAD3 phosphorylation increased later, with a significant elevation at 6 weeks. c-Myc, NF-κB and SMAD3 activation, respectively, correlated with repression of miR-29b and miR-29c at 10 days of obstruction and with repression of miR-29c at 6 weeks. An mRNA microarray analysis showed that the reduction of miR-29 following outlet obstruction was associated with increased levels of miR-29 target mRNAs, including mRNAs for tropoelastin, the matricellular protein Sparc and collagen IV. Outlet obstruction increased protein levels of eight out of eight examined miR-29 targets, including tropoelastin and Sparc. Transfection of human bladder smooth muscle cells with antimiR-29c and miR-29c mimic caused reciprocal changes in target protein levels in vitro. Tamoxifen inducible and smooth muscle-specific deletion of Dicer in mice reduced miR-29 expression and increased tropoelastin and the thickness of the basal lamina surrounding smooth muscle cells in the bladder. It also increased detrusor stiffness independent of outlet obstruction. Taken together, our study supports a model where the combined repressive influences of c-Myc, NF-κB and SMAD3 reduce miR-29 in bladder outlet obstruction, and where the resulting drop in miR-29 contributes to matrix remodeling and altered passive mechanical properties of the detrusor.
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