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Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells.

ABSTRACT: MicroRNA-124 (miR-124) has been reported to be downregulated in the cells exposed to hypoxia, which was confirmed in our study. We then used online microRNA target prediction tools to identify GRB2, SMAD5, and JAG1 as the candidate target genes of miR-124, and we next validated GRB2 as a direct gene by using luciferase reporter system. We also established the regulatory relationship between miR-124 and GRB2 by showing the negative linear relationship between GRB2 and miR-124 expression. Furthermore, we investigated the miR-124 and GRB2 expression levels of different genotypes including CC (n=30), GC (n=18), and GG (n=4), which supported the hypothesis that the presence of minor allele (C) of rs531564 polymorphism compromised the expression of miR-124. Meanwhile, we also conducted real-time polymerase chain reaction and Western blot analysis to study the expression of GRB2 among different genotypes or pulmonary artery smooth muscle cells (PASMCs) treated with miR-124 mimics, GRB2 small interfering RNA, and miR-124 inhibitors, respectively, and found that introduction of miR-124 or GRB2 small interfering RNA could reduce the expression of GRB2 and inhibit the proliferation of PASMCs, while miR-124 upregulated the expression of GRB2 and promoted the proliferation of PASMCs. A total of 412 COPD patients with PAH (n=182) or without PAH (n=230) were recruited in this study, and more individuals carrying at least one minor allele of rs531564 were found in the COPD patients with PAH than in those without PAH (odds ratio: 0.61, 95% confidence interval: 0.41-0.91; P=0.166). In conclusion, the presence of rs531564 minor allele may increase the risk of PAH in COPD by reducing miR-124 expression, increasing GRB2 expression, and promoting the proliferation of PASMCs.

SUBMITTER: Li Q

PROVIDER: S-EPMC5422315 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells.

Li Quanzhong Q Qian Zongjie Z Wang Linqing L

International journal of chronic obstructive pulmonary disease 20170504

MicroRNA-124 (miR-124) has been reported to be downregulated in the cells exposed to hypoxia, which was confirmed in our study. We then used online microRNA target prediction tools to identify GRB2, SMAD5, and JAG1 as the candidate target genes of miR-124, and we next validated GRB2 as a direct gene by using luciferase reporter system. We also established the regulatory relationship between miR-124 and GRB2 by showing the negative linear relationship between GRB2 and miR-124 expression. Furtherm ...[more]

PMID: 28496318

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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

Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells.

Publications

Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells.

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