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

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.