Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
J Cell Biochem. 2012 Apr;113(4):1198-207. doi: 10.1002/jcb.23452.
Abnormal proliferation, migration, and phenotypic modulation of vascular smooth muscle cells (VSMCs) are critical factors in neointima formation during restenosis. The purpose of this study is to determine the efficacy and possible cell signaling mechanisms of apigenin in VSMC activation induced by platelet-derived growth factor (PDGF)-BB and injury-induced neointima formation. Our data revealed a dose-dependent apigenin inhibition of PDGF-BB-induced proliferation of VSMCs by arresting cells in G0/G1-phase of the cell cycle as determined using 5-bromo-2'-deoxyuridine incorporation and flow cytometry. This was associated with the inhibition of cyclin-dependent kinase (CDK) 4,6 expression and an increase in p27Kip1 levels in PDGF-stimulated VSMCs. Moreover, apigenin was also found to regulate PDGF-induced migration and expression of smooth-muscle-specific contractile markers. Mechanistically, the PDGF-BB-induced phosphorylation of PDGF-receptor β (PDGF-Rβ), Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3) is negatively modulated by apigenin. For the in vivo studies using a mouse carotid arterial injury model, the administration of apigenin resulted in a significant inhibition of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells. These results demonstrate that apigenin can suppress PDGF-induced VSMC activation and neointima hyperplasia after vascular injury; these beneficial effects are probably the result of the blockade of PDGF-Rβ phosphorylation and its downstream signal transduction, including the Akt/GSK-3β, ERK1/2, and STAT3 pathways. The results suggest that apigenin may be a potential therapeutic candidate for the prevention of restenosis.
血管平滑肌细胞（VSMC）的异常增殖、迁移和表型调节是再狭窄过程中新生内膜形成的关键因素。本研究旨在确定芹菜素在血小板衍生生长因子（PDGF）-BB 诱导的 VSMC 激活和损伤诱导的新生内膜形成中对 VSMC 激活的疗效和可能的细胞信号机制。我们的数据显示，芹菜素呈剂量依赖性抑制 PDGF-BB 诱导的 VSMC 增殖，通过 5-溴-2'-脱氧尿苷掺入和流式细胞术确定细胞周期 G0/G1 期细胞阻滞。这与 cyclin-dependent kinase (CDK) 4,6 表达的抑制和 PDGF 刺激的 VSMC 中 p27Kip1 水平的增加有关。此外，还发现芹菜素可调节 PDGF 诱导的迁移和平滑肌特异性收缩标志物的表达。从机制上讲，PDGF-BB 诱导的 PDGF 受体β（PDGF-Rβ）、Akt/糖原合酶激酶（GSK）3β、细胞外信号调节激酶 1/2（ERK1/2）和信号转导子和转录激活子 3（STAT3）的磷酸化被芹菜素负调节。在使用小鼠颈动脉损伤模型的体内研究中，芹菜素的给药导致新生内膜/中膜比和增殖细胞核抗原（PCNA）阳性细胞显著抑制。这些结果表明，芹菜素可抑制血管损伤后 PDGF 诱导的 VSMC 激活和新生内膜增生；这些有益作用可能是由于阻断 PDGF-Rβ 磷酸化及其下游信号转导，包括 Akt/GSK-3β、ERK1/2 和 STAT3 途径。结果表明，芹菜素可能是预防再狭窄的潜在治疗候选物。
