The miR-182/Myadm axis regulates hypoxia-induced pulmonary hypertension by balancing the BMP- and TGF-β-signalling pathways in an SMC/EC-crosstalk-associated manner

• Published in: Basic research in cardiology Vol. 116; no. 1; p. 53
• Main Authors: Bai, Yongyi, Wang, Jingrong, Chen, Ying, Lv, Tingting, Wang, Xiaojian, Liu, Chunlei, Xue, Hao, He, Kunlun, Sun, Lan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2021; Springer Nature B.V
• Subjects: Bone marrow; Bone Morphogenetic Proteins; Cardiology; Crosstalk; Cyclic GMP; Endothelial Cells; Growth factors; Humans; Hypertension; Hypertension, Pulmonary - genetics; Hypoxia; Id1 protein; Medicine; Medicine & Public Health; MicroRNAs - genetics; Muscles; Myelin and Lymphocyte-Associated Proteolipid Proteins; Original Contribution; Progenitor cells; Pulmonary arteries; Pulmonary Artery; Signal transduction; Signaling; Smad2 protein; Smad4 protein; Smooth muscle; Stem cells; Transcription; Transforming Growth Factor beta; Transforming growth factor-b; BMPR2; Crosstalk; Id1; miR-182; TGF-β; Myadm; Pulmonary vascular remodelling
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-021-00892-6

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.