Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway

Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs.微管稳定剂（Microtubule stabilizing agents, MTSA）已被证实可抑制血管平滑肌细胞（vascular smooth muscle cell, VSMC）的增殖与迁移，并能有效降低内膜增生与再狭窄的发生风险。埃博霉素（Epothilones, EPOs）作为一类非紫杉烷类微管稳定剂，此前被发现可通过细胞周期阻滞有效抑制VSMC增殖与内膜形成。然而，埃博霉素对过度增殖VSMC的凋亡调控作用——这可能是其减轻内膜形成的潜在途径——以及其与VSMC存活相关的作用机制，迄今尚未明确。本研究旨在探究埃博霉素是否可通过诱导球囊损伤大鼠颈动脉内膜增生区域的细胞凋亡，进而抑制内膜形成，并阐明其潜在的作用机制。实验结果显示，EPO-B与EPO-D处理可显著诱导过度增殖VSMC发生细胞凋亡与有丝分裂灾难，从而抑制细胞增殖。进一步研究表明，埃博霉素可通过激活p53依赖型细胞凋亡信号通路（Bax/细胞色素c/caspase-3），显著抑制VSMC增殖并诱导其凋亡。本团队还证实，在大鼠颈动脉损伤模型中，局部给予埃博霉素处理可通过诱导细胞凋亡，强效抑制内膜病变形成。本研究结果表明，埃博霉素可通过诱导过度增殖VSMC发生p53依赖型细胞凋亡，从而展现出强效的抗内膜增生活性。