Altered MicroRNA Expression Is Responsible for the Pro-Osteogenic Phenotype of Interstitial Cells in Calcified Human Aortic Valves.
Altered MicroRNA Expression Is Responsible for the Pro-Osteogenic Phenotype of Interstitial Cells in Calcified Human Aortic Valves.
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MicroRNA 表达的改变是导致钙化人主动脉瓣间质细胞促成骨表型的原因。
DOI：
10.1161/jaha.116.005364
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发表时间：
2017-04-24
影响因子：
5.4
通讯作者：
Meng X
中科院分区：
文献类型：
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作者：
Song R;Fullerton DA;Ao L;Zhao KS;Reece TB;Cleveland JC Jr;Meng X
主动脉瓣间质细胞(AVICs)向肌成纤维细胞和成骨细胞样表型的转化在钙化性主动脉瓣疾病的进展中起着关键作用。一些microRNAs(MiRs)参与了干细胞向成骨细胞的分化。我们假设，表观遗传机制调节瓣膜促成骨活性。这项研究检测了钙化瓣膜AVIC中的miR谱，并确定了与AVIC表型转换有关的miR。从正常瓣膜和病变瓣膜分离出AVICs。MiR芯片分析显示，在疾病的AVIC中，有14个上调的miR和12个下调的miR。MIR486的升高和MIR204水平的降低与肌成纤维细胞生物标记物α-平滑肌肌动蛋白和成骨细胞生物标记物Runt相关转录因子2(Runx2)和osterix(Osx)的水平升高有关。将miR-486antagomir和miR-204模拟物共转染病肺血管内皮细胞，降低了其表达Runx2和OSX的能力。MiR486通过蛋白激酶B途径模拟α-平滑肌肌动蛋白在正常AVICs中的表达，并适度上调Runx2和Osx的水平。敲除α-平滑肌肌动蛋白可减弱miR-486诱导的Runx2和OSx的表达。MiR-486模拟物和miR-204拮抗剂协同促进正常AVICs和正常主动脉瓣组织中Runx2和OSX的表达和钙沉积。在钙化瓣膜的动静脉内皮细胞中，miR-486水平升高可诱导肌成纤维细胞转化为上调Runx2和OSX的表达，并与miR-204缺乏协同作用，从而提高细胞和瓣膜的成骨活性。这些新的发现表明，调节瓣膜促成骨活性的表观遗传机制对于预防钙化性主动脉瓣疾病的进展具有治疗潜力。
The transition of aortic valve interstitial cells (AVICs) to myofibroblastic and osteoblast‐like phenotypes plays a critical role in calcific aortic valve disease progression. Several microRNAs (miRs) are implicated in stem cell differentiation into osteoblast. We hypothesized that an epigenetic mechanism regulates valvular pro‐osteogenic activity. This study examined miR profile in AVICs of calcified valves and identified miRs responsible for AVIC phenotypic transition. AVICs were isolated from normal and diseased valves. The miR microarray analysis revealed 14 upregulated and 12 downregulated miRs in diseased AVICs. Increased miR‐486 and decreased miR‐204 levels were associated with higher levels of myofibroblastic biomarker α‐smooth muscle actin and osteoblastic biomarkers runt‐related transcription factor 2 (Runx2) and osterix (Osx). Cotransfection of miR‐486 antagomir and miR‐204 mimic in diseased AVICs reduced their ability to express Runx2 and Osx. The miR‐486 mimic upregulated α‐smooth muscle actin expression in normal AVICs through the protein kinase B pathway and moderately elevated Runx2 and Osx levels. Knockdown of α‐smooth muscle actin attenuated Runx2 and Osx expression induced by miR‐486. The miR‐486 mimic and miR‐204 antagomir synergistically promoted Runx2 and Osx expression and calcium deposition in normal AVICs and normal aortic valve tissue. In AVICs of calcified valves, increased levels of miR‐486 induce myofibroblastic transition to upregulate Runx2 and Osx expression and synergize with miR‐204 deficiency to elevate cellular and valvular pro‐osteogenic activity. These novel findings indicate that modulation of the epigenetic mechanism underlying valvular pro‐osteogenic activity has therapeutic potential for prevention of calcific aortic valve disease progression.