PDF(Pubmed)
Abstract：
Yohimbine (YHB) has been reported to possess anti-inflammatory, anticancer, and cardiac function-enhancing properties. Additionally, it has been reported to inhibit the proliferation, migration, and neointimal formation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) stimulation by suppressing the phospholipase C-gamma 1 pathway. However, the transcriptional regulatory mechanism of YHB controlling the behavior of VSMCs is not fully understood. In this study, YHB downregulated the expression of cell cycle regulatory proteins, such as proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinase 4 (CDK4), and cyclin E, by modulating the transcription factor FOXO3a in VSMCs induced by PDGF. Furthermore, YHB decreased p-38 and mTOR phosphorylation in a dose-dependent manner. Notably, YHB significantly reduced the phosphorylation at Y397 and Y925 sites of focal adhesion kinase (FAK), and this effect was greater at the Y925 site than Y397. In addition, the expression of paxillin, a FAK-associated protein known to bind to the Y925 site of FAK, was significantly reduced by YHB treatment in a dose-dependent manner. A pronounced reduction in the migration and proliferation of VSMCs was observed following co-treatment of YHB with mTOR or p38 inhibitors. In conclusion, this study shows that YHB inhibits the PDGF-induced proliferation and migration of VSMCs by regulating the transcription factor FOXO3a and the mTOR/p38/FAK signaling pathway. Therefore, YHB may be a potential therapeutic candidate for preventing and treating cardiovascular diseases such as atherosclerosis and vascular restenosis.
摘要：
据报道，育亨宾(YHB)具有抗炎作用，抗癌，和心脏功能增强特性。此外,据报道，它可以抑制增殖，迁移,和血小板衍生生长因子（PDGF）刺激通过抑制磷脂酶C-γ1途径诱导的血管平滑肌细胞（VSMC）的新内膜形成。然而,YHB控制VSMC行为的转录调控机制尚不完全清楚。在这项研究中,YHB下调细胞周期调控蛋白的表达，如增殖细胞核抗原（PCNA），细胞周期蛋白D1，细胞周期蛋白依赖性激酶4（CDK4），和细胞周期蛋白E，通过调节PDGF诱导的VSMC中的转录因子FOXO3a。此外，YHB以剂量依赖性方式降低p-38和mTOR磷酸化。值得注意的是,YHB显著降低粘着斑激酶(FAK)的Y397和Y925位点的磷酸化,Y925位点的这种影响大于Y397。此外,Paxillin的表达，一种已知与FAK的Y925位点结合的FAK相关蛋白，YHB治疗以剂量依赖性方式显着降低。在YHB与mTOR或p38抑制剂共同处理后,观察到VSMC的迁移和增殖的显著降低。总之,本研究表明YHB通过调节转录因子FOXO3a和mTOR/p38/FAK信号通路抑制PDGF诱导的VSMCs增殖和迁移。因此,YHB可能是预防和治疗心血管疾病如动脉粥样硬化和血管再狭窄的潜在治疗候选物。
