Sollott S J, Cheng L, Pauly R R, Jenkins G M, Monticone R E, Kuzuya M, Froehlich J P, Crow M T, Lakatta E G, Rowinsky E K
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Clin Invest. 1995 Apr;95(4):1869-76. doi: 10.1172/JCI117867.
Despite significant improvements in the primary success rate of the medical and surgical treatments for atherosclerotic disease, including angioplasty, bypass grafting, and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of individuals. Restenosis and the later stages in atherosclerotic lesions are due to a complex series of fibroproliferative responses to vascular injury involving potent growth-regulatory molecules (such as platelet-derived growth factor and basic fibroblast growth factor) and resulting in vascular smooth muscle cell (VSMC) proliferation, migration, and neointimal accumulation. We show here, based on experiments with both taxol and deuterium oxide, that microtubules are necessary for VSMCs to undergo the multiple transformations contributing to the development of the neointimal fibroproliferative lesion. Taxol was found to interfere both with platelet-derived growth factor-stimulated VSMC migration and with VSMC migration and with VSMC proliferation, at nanomolar levels in vitro. In vivo, taxol prevented medial VSMC proliferation and the neointimal VSMC accumulation in the rat carotid artery after balloon dilatation and endothelial denudation injury. This effect occurred at plasma levels approximately two orders of magnitude lower than that used clinically to treat human malignancy (peak levels achieved in this model were approximately 50-60 nM). Taxol may therefore be of therapeutic value in preventing human restenosis with minimal toxicity.
尽管在动脉粥样硬化疾病的医学和外科治疗（包括血管成形术、搭桥手术和动脉内膜切除术）的初次成功率方面有了显著提高，但由于晚期再狭窄导致的二次失败仍在30%至50%的个体中发生。再狭窄和动脉粥样硬化病变的后期阶段是由于对血管损伤的一系列复杂的纤维增生反应，涉及强大的生长调节分子（如血小板衍生生长因子和碱性成纤维细胞生长因子），并导致血管平滑肌细胞（VSMC）增殖、迁移和内膜下积聚。我们在此基于紫杉醇和重水的实验表明，微管对于VSMC经历促成内膜下纤维增生性病变发展的多种转变是必要的。在体外，纳摩尔水平的紫杉醇被发现既能干扰血小板衍生生长因子刺激的VSMC迁移，又能干扰VSMC迁移和VSMC增殖。在体内，紫杉醇可防止大鼠颈动脉球囊扩张和内皮剥脱损伤后中膜VSMC增殖和内膜下VSMC积聚。这种效应发生时的血浆水平比临床上用于治疗人类恶性肿瘤的水平低约两个数量级（该模型中达到的峰值水平约为50 - 60 nM）。因此，紫杉醇可能在以最小毒性预防人类再狭窄方面具有治疗价值。
