Pires Nuno M M, Eefting Daniel, de Vries Margreet R, Quax Paul H A, Jukema J Wouter
TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands.
Heart. 2007 Aug;93(8):922-7. doi: 10.1136/hrt.2006.102244. Epub 2007 Apr 20.
Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist.
To investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries.
Atherosclerotic lesions were induced by placement of a perivascular cuff around the femoral artery of hypercholesterolaemic ApoE*3-Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. The vascular pathological effects were evaluated after two additional weeks.
Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses showed that local delivery of sirolimus has no significant adverse effects on vascular disease. Conversely, high dosages of paclitaxel significantly increased apoptosis, internal elastic lamina disruption, and decreased medial and intimal smooth muscle cells and collagen content. Moreover, transcriptional analysis by real-time RT-PCR showed an increased level of pro-apoptotic mRNA transcripts (FAS, BAX, caspase 3) in paclitaxel-treated arteries.
Sirolimus and paclitaxel are effective in preventing restenosis. Sirolimus has no significant effect on arterial disease. In contrast, paclitaxel at high concentration demonstrated adverse vascular pathology and transcriptional responses, suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents is becoming more common in DES technology, this factor is important, given that higher dosages of paclitaxel may lead to increased apoptosis in the vessel wall and, consequently, to a more unstable phenotype of the pre-existing atherosclerotic lesion.
药物洗脱支架（DES）已成功应用于临床实践以预防血管成形术后再狭窄。然而，对DES安全性的担忧仍然存在。
在潜在病变的动脉粥样硬化动脉再狭窄的小鼠模型中，研究西罗莫司和紫杉醇对血管病理及转录反应的影响。
通过在高胆固醇血症ApoE*3-Leiden转基因小鼠的股动脉周围放置血管套环诱导动脉粥样硬化病变。两周后，将这些套环替换为西罗莫司或紫杉醇洗脱套环。再过两周后评估血管病理效应。
两种抗再狭窄化合物均显著抑制动脉粥样硬化斑块上再狭窄病变的进展。血管组织病理学分析表明，局部递送西罗莫司对血管疾病无显著不良影响。相反，高剂量紫杉醇显著增加细胞凋亡、内弹性膜破坏，并减少中膜和内膜平滑肌细胞及胶原蛋白含量。此外，实时RT-PCR转录分析显示，紫杉醇处理的动脉中促凋亡mRNA转录本（FAS、BAX、半胱天冬酶3）水平升高。
西罗莫司和紫杉醇在预防再狭窄方面有效。西罗莫司对动脉疾病无显著影响。相比之下，高浓度紫杉醇显示出不良的血管病理和转录反应，表明这种强效药物的治疗范围较窄。由于在DES技术中重叠支架使用越来越普遍，鉴于高剂量紫杉醇可能导致血管壁细胞凋亡增加，从而导致原有动脉粥样硬化病变的表型更不稳定，这一因素很重要。
