Abstract
This paper explores the potential mechanism of microRNA-143–5p regulation effects on pulmonary artery smooth muscle cells (PASMCs) functions in hypoxic pulmonary hypertension (HPH) via targeting HIF-1α, which may offer a new idea for HPH therapy. PASMCs were transfected with mimics control/miR-143–5p mimics or inhibitor control/miR-143–5p inhibitor. We used Western blotting and RT-qPCR to detect the protein and mRNA expressions, CCK-8 assay to detect cellular viability, Annexin V-FITC/PI staining and caspase-3/cleaved caspase-3 protein to evaluate cellular apoptosis, transwell migration experiment for cellular migration measurement and Dual luciferase reporter gene assay to prove the target of miR-143–5p. Cells under hypoxic condition presented the decreased protein and mRNA expressions of α-smooth muscle actin (SM-α-actin), Myocardin, smooth muscle myosin heavy chain (SMMHC), and smooth muscle-22α (SM22α), Calponin1 and Hypoxia-inducible factor-1α(HIF-1α), the increased cell viability and miR-143–5p level; Over-expression of miR-143–5p obviously reduced vascular smooth muscle-specific contraction marker protein levels and cellular apoptosis, increased cellular migration of PASMCs with hypoxia stimulation; Low-expression of miR-143–5p caused the opposite changes, while co-transfected with Si HIF-1α blocked the beneficial effects of miR-143–5p inhibition on PASMCs under hypoxia. MicroRNA-143–5p can promote the phenotype conversion, proliferation and migration of pulmonary artery smooth muscle cells under hypoxic condition through direct targeting of HIF-1α.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Albinson S and Sward K 2013 Targeting smooth muscle microRNAs for therapeutic benefit in vascular disease. Pharmacol. Res. 75 28–36
Ball MK, Waypa GB, Mungai PT, Nielsen JM, Czech L, Dudley VJ, Beussink L, Dettman RW, et al. 2014 Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha. Am. J. Respir. Crit. Care Med. 189 314–324
Bhattachariya A, Dahan D, Ekman M, Boettger T, Braun T, Swärd K, Hellstrand P and Albinsson S 2015 Spontaneous activity and stretch-induced contractile differentiation are reduced in vascular smooth muscle of miR-143/145 knockout mice. Acta Physiol. 215 133–143
Blum JI, Bijli KM, Murphy TC, Kleinhenz JM and Hart CM 2016 Time-dependent PPARgamma modulation of HIF-1alpha signaling in hypoxic pulmonary artery smooth muscle cells. Am. J. Med. Sci. 352 71–79
Bockmeyer CL, Maegel L, Janciauskiene S, Rische J, Lehmann U, Maus UA, Nickel N, Haverich A, et al. 2012 Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J. Heart Lung Transplant 31 764–772
Cordes KR, Shehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, et al. 2009 miR-145and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460 705–710
Davis-Dusenbery BN, Chan MC, Reno KE, Weisman AS, Layne MD, Lagna G and Hata A 2011 Down-regulation of krüppel-like factor-4 (KLF4)by microRNA-143/145is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. J. Biol. Chem. 286 28097–28110
Deng L, Blanco FJ, Stevens H, Lu, R, Caudrillier A, McBride M, McClure JD, Grant J, et al. 2015 MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ. Res. 117 870–883
Han CF, Li ZY and Li TH 2017 Roles of hypoxia-inducible factor-1alpha and its target genes in neonatal hypoxic pulmonary hypertension. Eur. Rev. Med. Pharmacol. Sci. 21 4167–4180
Hwang AR, Han JH, Lim JH, Kang YJ and Woo CH 2017 Fluvastatin inhibits age-induced cell proliferation and migration via an erk5-dependent nrf2 pathway in vascular smooth muscle cells. PLoS One 12 e0178278
Jiang B-H, Rue E, Wang GL, Roe R and Semenza GL 1996 Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. 271 17771–17778
Lee HJ, Jung YH, Choi GE, Kim JS, Chae CW and Han HJ 2019 Role of hif1alpha regulatory factors in stem cells. Int. J. Stem Cells 12 8–20
Marsboom G and Archer SL 2008 Pathways of proliferation: new targets to inhibit the growth of vascular smooth muscle cells. Circ. Res. 103 1047–1049
Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, et al. 2013 Pulmonary hypertension in chronic lung diseases. J. Am. Coll. Cardiol. 62 (25 suppl) D109–D116
Semenza GL 2000 HIF-1 and human disease: one highly involved factor. Genes Dev 14 1983–1991
Sutter CH, Laughner E and Semenza GL 2000 Hypoxia-inducible factor 1 protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc. Natl. Acad. Sci. USA 97 4748–4753
Taichman DB and Mandel J 2013 Epidemiology of pulmonary arterial hypertension. Clin. Chest. Med. 34 619–637
Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA and Haworth SG 2009 Development and pathology of pulmonary hypertension. J. Am. Coll. Cardiol. 54 S3–S9
Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL and Shimoda LA 2006 Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ. Res. 98 1528–1537
Wang L, Zheng J, Du Y, Huang Y, Li J, Liu B, Liu CJ, Zhu Y, et al. 2012 Cartilage oligomeric matrix protein maintains the contractile phenotype of vascular smooth muscle cells by interacting with alpha(7)beta(1) integrin. Circ. Res.106 514–525
Wang L, Zhou Y, Li M and Zhu Y 2014 Expression of hypoxia-inducible factor-1alpha, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension. Exp. Ther. Med. 8 335–339
Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, Regan E, Bailey WC, et al. 2012 Pulmonary arterial enlargement and acute exacerbations of COPD. N. Engl. J. Med. 367 913–921
Yu Z, Liu Y, Zhu J, Han J, Tian X, Han W and Zhao L 2019 Insights from molecular dynamics simulations and steered molecular dynamics simulations to exploit new trends of the interaction between hif-1alpha and p300. J. Biomol. Struct. Dyn. 38 1–12
Yue Y, Zhang Z, Zhang L, Chen S, Guo Y and Hong Y 2018 Mir-143 and mir-145 promote hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells through regulating abca1 expression. Cardiovasc. Pathol. 37 15–25
Zhang W, Liu D, Han X,, Ren J, Zhou P and Ding P 2019 Microrna-451 inhibits vascular smooth muscle cell migration and intimal hyperplasia after vascular injury via ywhaz/p38 MAPK pathway. Exp. Cell Res. 379 214–224
Zhang W, Zhu T, Wu W, Ge X, Xiong X, Zhang Z and Hu Ce 2018 LOX-1 mediated phenotypic switching of pulmonary arterial smooth muscle cells contributes to hypoxic pulmonary hypertension. Eur. J. Pharmacol. 818 84–95
Zhou W, Dasgupta C, Negash S, Liu J and Raj JU 2007 Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: Role of cGMP-dependent protein kinase. Am. J. Physiol. Lung Cell. Mol. Physiol. 292 L1459–L1466
Acknowledgements
The work was supported by Major projects of Natural Science Research in Colleges and Universities of Anhui Province (No. KJ2018ZD023), The Natural Science Foundation of Anhui province (No. 1908085QH353) and Anhui Province Education Key Projects (No. SK2018A1069).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by GAGANDEEP KANG.
Corresponding editor: Gagandeep Kang
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Tang, B., Tang, Mm., Xu, Qm. et al. MicroRNA-143–5p modulates pulmonary artery smooth muscle cells functions in hypoxic pulmonary hypertension through targeting HIF-1α. J Biosci 45, 37 (2020). https://doi.org/10.1007/s12038-020-9992-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12038-020-9992-1