title: MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3.
abstract: MicroRNAs (miRNAs) play important roles in pulmonary artery hypertension (PAH). Recently, it has been reported that miR-199a-5p participates in the progression of chronic obstructive pulmonary disease, ventricular hypertrophy and heart failure. However, the roles of miR-199a-5p in PAH are still unclear. In the present study, miR-199a-5p was investigated in PAH rat models and in human pulmonary artery smooth muscle cells (HPASMCs) and endothelial cells (HPAECs). The expression of miR-199a-5p was significantly increased following PAH induction, and anti-miR-199a-5p could increase the nitric oxide (NO) level and decrease the PAH-induced upregulation of pulmonary artery pressure and right ventricular hypertrophy. Moreover, in HPASMCs and HPAECs, miR-199a-5p overexpression could inhibit the level of NO and promote the concentration of Ca(2+), but anti-miR-199a-5p showed opposite results. Further analysis demonstrated that miR-199a-5p attenuated the expression of Smad3. Importantly, Smad3 was confirmed to be the target gene of miR-199a-5p using dual-luciferase reporter assay. Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. Moreover, in PAH model, Smad3, p-Smad3 and Smad4 were all downregulated in lung tissues, and SIS3 (Smad3 inhibitor) could reverse the effects of anti-miR-199a-5p in PAH rats. Our date suggest that miR-199a-5p may function as a regulator of PAH by targeting Smad3, indicating a novel therapeutic strategy for patients with PAH.
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of ZhengZhou University, ZhengZhou 450052, China.
authors.forename: Yuanhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of ZhengZhou University, ZhengZhou 450052, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of ZhengZhou University, ZhengZhou 450052, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of ZhengZhou University, ZhengZhou 450052, China. Electronic address: jingwangcc@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D008168:Lung / Q000503:physiopathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D035683:MicroRNAs; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C531408:mirn199 microRNA, human; D009569:Nitric Oxide; D002118:Calcium
keywords: Calcium concentration; Nitric oxide; Pulmonary artery hypertension; Smad3; miR-199a-5p