O'Neill Sean M, Olympia Dina K, Fox Todd E, Brown J Tony, Stover Thomas C, Houck Kristy L, Wilson Ronald, Waybill Peter, Kozak Mark, Levison Steven W, Weber Norbert, Karavodin Linda M, Kester Mark
Department of Pharmacology, Penn State College of Medicine, Hershey, PA.
Vasc Dis Prev. 2008 Aug 1;5(3):200-210. doi: 10.2174/156727008785133809.
Drug eluting stents have recently been associated with the increased risk of adverse thrombogenic events and/or late luminal loss, which is highly associated with incomplete re-endothelialization. The increased risks behoove the design of alternative delivery modalities and/or drugs that do not compromise the re-endotheliaization process. The objective of the present study is to elucidate the biological mechanism(s) by which non-stent-based delivery modalities for the anti-proliferative lipid metabolite, C(6)-ceramide, could lead to a reduction in arterial injury after angioplasty. RESULTS: Immunohistochemical studies in rabbit and porcine models suggest that C(6)-ceramide-coated balloon catheters limit arterial stenosis without inhibiting endothelial wound healing responses. Specifically, C(6)-ceramide-coated balloon catheters reduce internal elastica injury with a corresponding reduction in medial fracture length in a 28-day porcine coronary artery stretch model. In addition, C(6)-ceramide decreases the formation of the fibrin matrix to possibly augment the subsequent wound healing response. We hypothesized that differential metabolism of exogenous ceramide by coronary endothelial and smooth muscle cells could explain the apparent discrepancy between the anti-proliferative actions of ceramide and the pro-wound healing responses of ceramide. Human coronary artery endothelial cells (HCAEC), in contrast to human coronary artery smooth muscle cells (HCASMC), preferentially express ceramide kinase and form ceramide-1-phosphate, which promotes endothelial cell survival. CONCLUSION: Differential metabolism of ceramide between HCASMC and HCAEC offers a mechanism by which ceramide preferentially limits smooth muscle cell growth, in the presence of active wound healing. The combinatorial ability of ceramide to limit vascular smooth muscle proliferation and promote re-endothelialization, offers the potential for C(6)-ceramide-coated catheters to serve as adjuncts to stent-based modalities or as a stand-alone treatment.
药物洗脱支架最近与不良血栓形成事件风险增加和/或晚期管腔丢失相关，这与内皮再内皮化不完全高度相关。这些增加的风险促使人们设计不影响再内皮化过程的替代递送方式和/或药物。本研究的目的是阐明基于非支架的抗增殖脂质代谢物C(6)-神经酰胺递送方式可导致血管成形术后动脉损伤减少的生物学机制。结果：在兔和猪模型中的免疫组织化学研究表明，涂有C(6)-神经酰胺的球囊导管可限制动脉狭窄，而不抑制内皮伤口愈合反应。具体而言，在28天的猪冠状动脉拉伸模型中，涂有C(6)-神经酰胺的球囊导管减少了内弹力膜损伤，同时相应减少了中膜断裂长度。此外，C(6)-神经酰胺减少了纤维蛋白基质的形成，可能增强了随后的伤口愈合反应。我们假设冠状动脉内皮细胞和平滑肌细胞对外源性神经酰胺的不同代谢可以解释神经酰胺的抗增殖作用与神经酰胺的促伤口愈合反应之间明显的差异。与人类冠状动脉平滑肌细胞（HCASMC）相比，人类冠状动脉内皮细胞（HCAEC）优先表达神经酰胺激酶并形成神经酰胺-1-磷酸，后者可促进内皮细胞存活。结论：HCASMC和HCAEC之间神经酰胺的不同代谢提供了一种机制，通过该机制，在存在活跃伤口愈合的情况下，神经酰胺优先限制平滑肌细胞生长。神经酰胺限制血管平滑肌增殖和促进再内皮化的联合能力，使涂有C(6)-神经酰胺的导管有可能作为基于支架的治疗方式的辅助手段或作为独立治疗方法。
