Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642, USA.
J Pharmacol Exp Ther. 2012 Nov;343(2):479-88. doi: 10.1124/jpet.112.195446. Epub 2012 Aug 22.
Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G1-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.
异常的血管平滑肌细胞 (SMC) 激活与各种血管疾病有关，如动脉粥样硬化、支架内再狭窄、静脉移植物疾病和移植相关血管病。长春西汀是长春胺的生物碱衍生物，长期以来一直被用作治疗认知障碍的脑血流增强剂。然而，其在病理性血管重构中的作用尚未被探索。在此，我们显示全身性给予长春西汀可显著减少结扎损伤后的颈动脉内膜新生。长春西汀还明显减少了人隐静脉外植体在离体培养中的自发性重构。在培养的 SMC 中，长春西汀剂量依赖性地抑制细胞增殖并导致 G1 期细胞周期停滞，这与细胞周期蛋白 D1 的减少和 p27Kip1 水平的增加有关。此外，长春西汀剂量依赖性地抑制血小板衍生生长因子 (PDGF) 刺激的 SMC 迁移，通过二维迁移测定和三维主动脉中膜外植体侵袭测定来确定。此外，长春西汀显著降低 PDGF 诱导的 I 型胶原蛋白和纤维连接蛋白表达。值得注意的是，长春西汀特异性抑制 PDGF 刺激的细胞外信号调节激酶 1/2 (ERK1/2) 磷酸化，但不抑制蛋白激酶 B。长春西汀有力地减弱了细胞内活性氧 (ROS) 的产生，这在很大程度上介导了长春西汀对 ERK1/2 激活和 SMC 生长的抑制作用。综上所述，我们的结果揭示了长春西汀在减轻内膜增生和病理性血管重构中的新功能，至少部分通过抑制 SMC 中 ROS 产生和 ERK1/2 激活来实现。鉴于长春西汀的安全性，本研究为长春西汀在增殖性血管疾病中的治疗潜力提供了新的见解。
