Digoxin inhibits PDGF-BB-induced VSMC proliferation and migration through an increase in ILK signaling and attenuates neointima formation following carotid injury.
Digoxin inhibits PDGF-BB-induced VSMC proliferation and migration through an increase in ILK signaling and attenuates neointima formation following carotid injury.
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DOI：
10.3892/ijmm.2015.2320
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发表时间：
2015-10
影响因子：
5.4
通讯作者：
Gu Y
中科院分区：
文献类型：
--
作者：
Yan G;Wang Q;Hu S;Wang D;Qiao Y;Ma G;Tang C;Gu Y
血管平滑肌细胞（VSMCs）增殖和迁移的增加是经皮冠状动脉介入治疗后动脉再狭窄发展的关键事件。地高辛长期以来一直用于治疗心力衰竭，并已被证明通过多种途径抑制癌细胞的增殖。然而，地高辛在调节VSMC增殖和迁移中的潜在作用及其在治疗心血管疾病（如再狭窄）中的有效性仍未被探索。在本研究中，我们证明地高辛诱导的生长抑制与血小板衍生生长因子（PDGF）刺激的VSMCs中CDK激活的下调和p27Kip1水平的恢复有关。此外，我们发现地高辛恢复了pdgf - bb诱导的对整合素连接激酶（ILK）表达的抑制，并阻止了pdgf - bb诱导的糖原合成酶激酶(GSK)-3β的激活。此外，地高辛抑制粘附分子和细胞外基质相关蛋白的表达。最后，我们发现地高辛显著抑制大鼠血管损伤后的新内膜形成，并伴有细胞增殖减少。地高辛的这些作用至少在一定程度上是通过pdgf - bb刺激的VSMCs中ILK/Akt信号的增加和GSK-3β信号的减少介导的。综上所述，我们的数据表明地高辛对pdgf - bb诱导的大鼠VSMCs的增殖、迁移和表型调节具有抑制作用，并阻止新生内膜的形成。这些观察结果表明地高辛在治疗心血管疾病（如再狭窄）中的潜在治疗应用。
The increased proliferation and migration of vascular smooth muscle cells (VSMCs) are key events in the development of artery restenosis following percutaneous coronary intervention. Digoxin has long been used in the treatment of heart failure and has been shown to inhibit the proliferation of cancer cells through multiple pathways. However, the potential role of digoxin in the regulation of VSMC proliferation and migration and its effectiveness in the treatment of cardiovascular diseases, such as restenosis, remains unexplored. In the present study, we demonstrate that digoxin-induced growth inhibition is associated with the downregulation of CDK activation and the restoration of p27Kip1 levels in platelet-derived growth factor (PDGF)-stimulated VSMCs. In addition, we found that digoxin restored the PDGF-BB-induced inhibition of integrin linked kinase (ILK) expression and prevented the PDGF-BB-induced activation of glycogen synthase kinase (GSK)-3β. Furthermore, digoxin inhibited adhesion molecule and extracellular matrix relative protein expression. Finally, we found that digoxin significantly inhibited neointima formation, accompanied by a decrease in cell proliferation following vascular injury in rats. These effects of digoxin were shown to be mediated, at least in part, through an increase in ILK/Akt signaling and a decrease in GSK-3β signaling in PDGF-BB-stimulated VSMCs. In conclusion, our data demonstrate that digoxin exerts an inhibitory effect on the PDGF-BB-induced proliferation, migration and phenotypic modulation of VSMCs, and prevents neointima formation in rats. These observations indicate the potential therapeutic application of digoxin in the treatment of cardiovascular diseases, such as restenosis.