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: 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.