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MiR?106b?5p modulates acute pulmonary embolism via NOR1 in pulmonary artery smooth muscle cells.

ABSTRACT: Acute pulmonary embolism (APE) is a common cause of acute cardiovascular failure and has a high morbidity and mortality rate. Inhibiting the excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) is a potential treatment strategy following an APE. Various microRNAs (miRNAs/miRs) have been shown to regulate cell proliferation, apoptosis and other physiological processes. However, the specific mechanisms underlying the action of multiple miRNAs are still not understood in APE. In the present study, the role of miR?106b?5p on APE was demonstrated in platelet?derived growth factor (PDGF)?induced PASMCs in vitro and in an APE?mouse model in vivo. The results showed that miR?106b?5p expression was downregulated in PDGF?induced PASMCs and APE mice, and NOR1 levels were upregulated. Proliferating cell nuclear antigen (PCNA) expression levels in cells and proliferation of PASMCs proliferation and migration were reduced following treatment with miR?106b?5p agomiR, and increased following treatment with miR?106b?5p antagomiR. miR?106b?5p targeted the 3' untranslated region of NOR?1 mRNA and reduced NOR1 expression. NOR1 overexpression reversed the effects of miR?106?5p on PDGF?induced PASMCs. The functional roles of miR?106b?5p in PDGF?induced PASMCs and an APE mouse?model, and the underlying molecular mechanisms were evaluated. AgomiR?106b?5p improved APE?induced mortality and pulmonary vascular proliferation in mice. These data suggest that miR?106?5p is a novel regulator of proliferation of PASMCs and of pulmonary vascular remodeling through PDGF?induced PASMCs in an APE mouse model via targeting NOR1. These results expand the understanding of the pathogenesis underlying APE and highlight potential novel therapeutic targets.

SUBMITTER: Chen H

PROVIDER: S-EPMC7138273 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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miR‑106b‑5p modulates acute pulmonary embolism via NOR1 in pulmonary artery smooth muscle cells.

Chen Heming H Ma Qiang Q Zhang Junbo J Meng Yan Y Pan Longfei L Tian Hongyan H

International journal of molecular medicine 20200309 5

Acute pulmonary embolism (APE) is a common cause of acute cardiovascular failure and has a high morbidity and mortality rate. Inhibiting the excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) is a potential treatment strategy following an APE. Various microRNAs (miRNAs/miRs) have been shown to regulate cell proliferation, apoptosis and other physiological processes. However, the specific mechanisms underlying the action of multiple miRNAs are still not underst ...[more]

PMID: 32323756

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Project description:The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.

Dataset Information

MiR?106b?5p modulates acute pulmonary embolism via NOR1 in pulmonary artery smooth muscle cells.

Publications

miR‑106b‑5p modulates acute pulmonary embolism via NOR1 in pulmonary artery smooth muscle cells.

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