Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 386, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2019.114827
Keywords
Pulmonary arterial hypertension; miR-181b-5p; Endothelial-mesenchymal transition; Endocan; TGFBRI
Categories
Funding
- Guide Project for Natural Science Foundation of Liaoning Province [20180551211]
- Construction Project for the Clinical Translation Medicine Research Center of Cardiovascular System and Hypertension Diseases of Liaoning Province [CB10]
- Construction Project for the Clinical Medicine Research Center of Rheumatic Diseases of Shenyang City [S512]
- Doctoral Startup Foundation of Liaoning Province [2019BS-288]
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Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-alpha, TGF beta 1 and IL-1 beta in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.
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