We recently identified oncologic miR-182 as a new regulator of pulmonary artery hypertension (PAH) that targets myeloid-associated differentiation marker (Myadm), which is expressed in bone marrow stem cells and multipotent progenitors. Both miR-182 and Myadm are expressed in the cardiopulmonary system and correlated with the balance between the bone morphogenetic protein (BMP) and the transforming growth factor (TGF)-β signalling pathways, which are disturbed in PAH. We hypothesize that miR-182/Myadm are involved in BMP-TGF-β-signalling way in PAH. Hypoxia triggered pathological progression in cardiopulmonary PAH in vivo and in vitro; these changes were accompanied by strongly dowregulated BMP/SMAD1/5/8 expression and enhanced TGF-β/SMAD2/3 signalling pathway, favouring SMAD4/SMAD2 transcript formation and inhibiting the PAH negative regulator Id1 expression. miR-182 gain-of-function significantly inhibited the pathological progression in hypoxia-induced PAH (HPH) in vivo and in vitro, with a restoration of the balance in BMP-TGF-β signalling pathway. This recovery was abrogated by overexpression of Myadm. Conversely, loss-of-function of miR-182 increased the pathological progression of HPH followed by severe disturbance of BMP and TGF-β signal transduction and reduced Id1 expression, which was restored by Myadm knockdown. We also showed that the miR-182/Myadm relate BMP-TGF-β pathway is associated with NOS3/NO/cGMP via the crosstalk between endothelial cells and smooth muscle cells. Our findings further support the therapeutic significance of miR-182/Myadm in PAH via the balance of BMP- and TGF-β-associated mechanisms.

我们最近将肿瘤学 miR-182 鉴定为一种新的肺动脉高压 (PAH) 调节剂，它靶向骨髓相关分化标志物 (Myadm)，它在骨髓干细胞和多能祖细胞中表达。miR-182 和 Myadm 均在心肺系统中表达，并与在 PAH 中受到干扰的骨形态发生蛋白 (BMP) 和转化生长因子 (TGF)-β 信号通路之间的平衡相关。我们假设 miR-182/Myadm 参与 PAH 中的 BMP-TGF-β 信号传导方式。缺氧在体内和体外引发心肺多环芳烃的病理进展；这些变化伴随着强烈下调的 BMP/SMAD1/5/8 表达和增强的 TGF-β/SMAD2/3 信号通路，有利于 SMAD4/SMAD2 转录物的形成并抑制 PAH 负调节因子 Id1 的表达。miR-182 功能获得在体内和体外显着抑制缺氧诱导的 PAH (HPH) 的病理进展，恢复 BMP-TGF-β 信号通路的平衡。这种恢复因 Myadm 的过度表达而被取消。相反，miR-182 的功能丧失增加了 HPH 的病理进展，随后严重干扰了 BMP 和 TGF-β 信号转导，并降低了 Id1 表达，而 Myadm 敲低恢复了这种情况。我们还表明，miR-182/Myadm 相关的 BMP-TGF-β 通路通过内皮细胞和平滑肌细胞之间的串扰与 NOS3/NO/cGMP 相关。