Dataset Information

Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells.

ABSTRACT:

Background

Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility.

Methods and results

Real-time quantitative reverse transcription-polymerase chain reaction assay proved that downregulation of miR-1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR-1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3'-untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR-1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR-1281. Mechanistically, it is found that platelet-derived growth factor BB activates the phosphatidylinositol 3-kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR-1281 expression. Finally, a reduced miR-1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline-induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease-pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR-1281.

Conclusions

Herein, we report a novel regulatory axis, phosphatidylinositol 3-kinase-DNA methyltransferase 1-miR-1281-histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet-derived growth factor BB-stimulated PASMC proliferation and migration and pulmonary vascular remodeling.

SUBMITTER: Li Y

PROVIDER: S-EPMC5907547 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells.

Li Yanjiao Y Li Li L Qian Zhengjiang Z Lin Boya B Chen Jidong J Luo Yixuan Y Qu Junle J Raj J Usha JU Gou Deming D

Journal of the American Heart Association 20180307 6

<h4>Background</h4>Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility.<h4>Methods and results< ...[more]

PMID: 29514810

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Project description:BackgroundThe progression rate of CKD varies substantially among patients. The genetic and epigenetic contributions that modify how individual patients respond to kidney injury are largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l has an antifibrotic effect by repressing Edn1, which encodes endothelin 1 in the connecting tubule/collecting duct.MethodsTo determine if deletion of the Dot1l gene is a genetic and epigenetic risk factor through regulating Edn1, we studied four groups of mice: wild-type mice, connecting tubule/collecting duct-specific Dot1l conditional knockout mice (Dot1lAC ), Dot1l and Edn1 double-knockout mice (DEAC ), and Edn1 connecting tubule/collecting duct-specific conditional knockout mice (Edn1AC ), under three experimental conditions (streptozotocin-induced diabetes, during normal aging, and after unilateral ureteral obstruction). We used several approaches (colocalization, glutathione S-transferase pulldown, coimmunoprecipitation, yeast two-hybrid, gel shift, and chromatin immunoprecipitation assays) to identify and confirm interaction of Dot1a (the major Dot1l splicing variant in the mouse kidney) with histone deacetylase 2 (HDAC2), as well as the function of the Dot1a-HDAC2 complex in regulating Edn1 transcription.ResultsIn each case, Dot1lAC mice developed more pronounced kidney fibrosis and kidney malfunction compared with wild-type mice. These Dot1lAC phenotypes were ameliorated in the double-knockout DEAC mice. The interaction between Dot1a and HDAC2 prevents the Dot1a-HDAC2 complex from association with DNA, providing a counterbalancing mechanism governing Edn1 transcription by modulating H3 K79 dimethylation and H3 acetylation at the Edn1 promoter.ConclusionsOur study confirms Dot1l to be a genetic and epigenetic modifier of kidney fibrosis, reveals a new mechanism regulating Edn1 transcription by Dot1a and HDAC2, and reinforces endothelin 1 as a therapeutic target of kidney fibrosis.

Dataset Information

Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells.

Background

Methods and results

Conclusions

Publications

Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells.

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