C(6)-Ceramide-Coated Catheters Promote Re-Endothelialization of Stretch-Injured Arteries.
C(6)-Ceramide-Coated Catheters Promote Re-Endothelialization of Stretch-Injured Arteries.
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DOI：
10.2174/156727008785133809
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发表时间：
2008-08-01
期刊：
影响因子：
--
通讯作者：
Kester M
中科院分区：
文献类型：
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作者：
O'Neill SM;Olympia DK;Fox TE;Brown JT;Stover TC;Houck KL;Wilson R;Waybill P;Kozak M;Levison SW;Weber N;Karavodin LM;Kester M
最近发现药物洗脱支架与不良血栓形成事件和/或晚期管腔丢失的风险增加相关，后者与不完全再内皮化高度相关。增加的风险理应设计不损害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抗增殖脂质代谢物C6-神经酰胺的非支架型递送方式可减少血管成形术后动脉损伤的生物学机制。兔和猪模型的免疫组织化学研究表明，C6-神经酰胺涂层球囊导管限制动脉狭窄，而不抑制内皮伤口愈合反应。具体而言，在28天猪冠状动脉拉伸模型中，C6-神经酰胺涂层球囊导管减少了内部弹性损伤，相应减少了内侧骨折长度。此外，C6-神经酰胺减少了纤维蛋白基质的形成，从而可能增强随后的伤口愈合反应。我们推测，外源性神经酰胺的差异代谢冠状动脉内皮细胞和平滑肌细胞可以解释神经酰胺的抗增殖作用和亲伤口愈合反应的神经酰胺之间的明显差异。与人冠状动脉平滑肌细胞（HCASMC）相比，人冠状动脉内皮细胞（HCAEC）优先表达神经酰胺激酶并形成神经酰胺-1-磷酸，其促进内皮细胞存活。HCASMC和HCAEC之间神经酰胺的差异代谢提供了一种机制，通过该机制，神经酰胺在主动伤口愈合的情况下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组合能力，为C6-神经酰胺涂层导管提供了作为支架治疗方式替代品或作为独立治疗的可能性。
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, C6-ceramide, could lead to a reduction in arterial injury after angioplasty. Immunohistochemical studies in rabbit and porcine models suggest that C6-ceramide-coated balloon catheters limit arterial stenosis without inhibiting endothelial wound healing responses. Specifically, C6-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, C6-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. 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 C6-ceramide-coated catheters to serve as adjuncts to stent-based modalities or as a stand-alone treatment.