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.
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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磷脂酰肌醇 3-激酶-DNA 甲基转移酶 1-miR-1281-组蛋白脱乙酰酶 4 调节轴介导血小板衍生生长因子诱导的肺动脉平滑肌细胞的增殖和迁移。
DOI：
10.1161/jaha.117.007572
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发表时间：
2018-03-07
影响因子：
5.4
通讯作者：
Gou D
中科院分区：
文献类型：
--
作者：
Li Y;Li L;Qian Z;Lin B;Chen J;Luo Y;Qu J;Raj JU;Gou D
血小板源性生长因子BB是肺动脉平滑肌细胞（PASMC）的一种强效有丝分裂原，与肺动脉重塑有关，肺动脉重塑是肺动脉高压的一个关键致病特征。先前在血小板衍生生长因子BB处理的PASMCs中的microRNA分析发现了显著下调的microRNA，miR-1281，但它与任何细胞功能无关，我们研究了这种可能性。真实的实时定量逆转录-聚合酶链反应试验证明miR-1281的下调在人和大鼠PASMCs中是一种保守现象。miR-1281在PASMCs中的过表达和抑制分别促进和抑制细胞增殖和迁移。生物信息学预测和3′-非翻译区报告基因分析确定组蛋白去乙酰化酶4是miR-1281的直接靶点。支持这一点的是，增殖和迁移试验证明组蛋白脱乙酰酶4的细胞功能与miR-1281的细胞功能呈负相关。从机制上讲，发现血小板衍生生长因子BB激活磷脂酰肌醇3激酶途径，然后诱导DNA甲基转移酶1的表达，导致侧翼CpG岛的甲基化增强和miR-1281表达抑制。最后，在体外缺氧PASMCs、野百合碱诱导的肺动脉高压大鼠的肺动脉和冠心病-肺动脉高压患者的血清中，一致确定了miR-1281水平降低。这些数据表明，miR-1281可能具有诊断和治疗用途。在此，我们报告了一种新的调节轴，磷脂酰肌醇3激酶-DNA甲基转移酶1-miR-1281-组蛋白脱乙酰酶4，整合了多种表观遗传调节因子，参与血小板源性生长因子BB刺激的PASMC增殖和迁移以及肺血管重塑。
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. 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. 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.