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    miR-34a改善肺动脉高压大鼠细胞外基质过度沉积的作用及机制

    Effect and Mechanism of miR-34a in Ameliorating Extracellular Matrix Accumulation in Monocrotaline-induced Pulmonary Arterial Hypertension

      摘要
    • 摘要:
      目的 探究微小RNA-34a(microRNA-34a，miR-34a)在细胞外基质(extracellular matrix，ECM)过度沉积和肺动脉高压(pulmonary arterial hypertension，PAH)发病机制中的分子调控机制。
      方法 大鼠腹腔注射野百合碱(monocrotaline，MCT)构建PAH模型；尾静脉注射miR-34a agomiR构建miR-34a过表达模型。此外，原代培养的大鼠肺动脉平滑肌细胞(pulmonary arterial smooth muscle cells，PASMCs)分别转染miR-34a inhibitor、基质金属蛋白酶2(matrix metalloproteinase 2，MMP-2)小干扰RNA(small interfering RNA，siRNA)，明确miR-34a和MMP-2在PASMCs的ECM过度沉积中的作用，并进一步探讨其潜在的分子机制。
      结果 miR-34a在MCT诱导PAH大鼠的肺组织中表达下调，过表达miR-34a改善MCT诱导PAH大鼠的ECM过度沉积和肺血管重塑。体外细胞实验发现，抑制miR-34a可增加PASMCs中MMP-2/组织金属蛋白酶抑制剂-2(tissue inhibitor of matrix metalloproteinases 2，TIMP-2)的比值和I型胶原蛋白的表达；敲除MMP-2可逆转由miR-34a表达减低引起的I型胶原蛋白上调。
      结论 过表达miR-34a可改善MCT诱导ECM过度沉积和肺血管重塑，提示上调miR-34a表达可能在预防和治疗PAH中具有潜在价值。

       

      Abstract:
      OBJECTIVE  To explore the molecular regulatory mechanisms of microRNA-34a(miR-34a) in the excessive deposition of extracellular matrix(ECM) and the pathogenesis of pulmonary arterial hypertension(PAH).
      METHODS Intraperitoneal injection of monocrotaline(MCT) was given to rats to induce the PAH model. miR-34a agomiR was administrated to rats by tail vein injection to establish the miR-34a over-expression model. In addition, miR-34a inhibitor, matrix metalloproteinase 2(MMP-2) small interfering RNA(siRNA) was transfected into primary cultured pulmonary arterial smooth muscle cells(PASMCs) respectively to examine the effect of miR-34a or MMP-2 on ECM accumulation in PASMCs and to further explore its underlying molecular mechanisms.
      RESULTS miR-34a was down-regulated in the lung tissues of MCT-induced PAH rats, and miR-34a over-expression ameliorated excessive ECM accumulation and pulmonary vascular remodeling in MCT-induced PAH rats. In addition, in vitro cell experiments found that inhibition of miR-34a increased the ratio of MMP-2/tissue inhibitor of matrix metalloproteinases 2(TIMP-2) and the expression of collagen I in PASMCs; and knockdown of MMP-2 reversed the up-regulation of collagen I protein induced by inhibition of miR-34a in PASMCs.
      CONCLUSION Over-expression of miR-34a ameliorates ECM accumulation in MCT-induced PAH, suggesting that elevating miR-34a expression level might be of potential value in the prevention and treatment of PAH.

       

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