Biologically Selective Drug-Eluting Stent

摘要： 金属支架通常被用来恢复狭窄冠状动脉的血流。裸金属支架 在高压下展开会导致血管壁和平滑肌细胞(SMC)的破坏， 随之而来的是SMC增殖、新生内膜增生和治疗失败。为了对抗支架内再狭窄， 提供mTOR抑制剂的药物洗脱支架，如西罗莫司或伊维洛莫斯，已成为标准护理 用于冠状动脉支架植入。然而，这些支架通常需要长期使用阿司匹林进行双重抗血小板治疗。 和Plavix(氯吡格雷)，以防止血栓闭塞的支架动脉节段。这是由于 MTOR抑制剂的相对非特异性作用：内皮损伤后不能有效恢复 Dess，使支架支柱和动脉管腔容易受到血小板活化和血栓形成的影响。 不幸的是，长期的双重抗血小板治疗导致出血/中风风险增加，矛盾的是， 增加心肌梗死的风险。因此，寻找一种替代药物洗脱策略，将节省 血管内皮细胞在防止再狭窄的同时，对冠心病患者将是非常有益的。 仍在研究中的一氧化氮(NO⋅)释放支架具有吸引力，因为它们 作用机制抑制SMC的生长，但不抑制EC的生长，并且由于没有⋅具有很短的扩散距离， 从而将其影响限制在局部区域。然而，到目前为止，还没有支架成功地输送到 足够剂量的NO-⋅可以可靠地抑制SMC的生长。既然没有⋅是SMC的选择性抑制剂，我们怎么能 提高它的效力？在这项工作中，我们利用了NO⋅增加SMC上Fas受体的事实 表面，而对EC没有类似的影响。Fas--与Fas结合后的死亡诱导信号复合体 配体(FasL)。已知Fas介导的SMC凋亡可显著减少损伤后SMC的增殖 船只。事实上，杀死SMC的Fas-FasL相互作用可能会产生比mTOR更强大的DES 抑制剂，因为抑制mTOR可以阻止细胞生长，但可能不会导致细胞凋亡。临床上，DES伴 更好的SMC抑制是迫切需要的，因为目前的DES仍然受到显著的支架置入率的影响 5年后再狭窄。由于SMC对Fas-FasL的相互作用明显比EC更敏感，我们 假设下一代支架同时输送FasL和NO有可能有效地阻断 内膜增生，同时保留EC活性，比其他DES更有效。这反过来又可以提供一个 如何缩短支架术后抗凝治疗，抑制支架内再狭窄，从而减少患者 冠状动脉支架置入后的风险。

ABSTRACT: Metallic stents are often used to restore blood flow in stenotic coronary arteries. Bare metal stent deployment under high pressure leads to vascular wall and smooth muscle cell (SMC) damage, with subsequent SMC proliferation, neointimal hyperplasia and treatment failure. To combat in-stent restenosis, drug-eluting stents delivering mTOR inhibitors such as sirolimus or everolimus, have become standard of care for coronary stenting. However, these stents typically require long-term dual anti-platelet therapy with aspirin and Plavix (clopidogrel), to prevent thrombotic occlusion of the stented arterial segment. This is due to the relatively non-specific action of mTOR inhibitors: endothelium does not efficiently recover after injury from DESs, rendering the stent struts and arterial lumen vulnerable to platelet activation and thrombosis. Unfortunately, long-term dual anti-platelet therapy leads to increased bleeding/stroke risk and, paradoxically, to increased risk of myocardial infarction. Therefore, finding an alternative drug elution strategy, that would spare endothelium while preventing re-stenosis, would be hugely beneficial to patients with coronary artery disease. Nitric oxide (NO⋅)-releasing stents, which are still under investigation, are attractive because their mechanism of action inhibits growth of SMC but not EC, and because NO⋅ has a very short diffusion distance, thereby limiting its effects to a localized region. However, to date no stent has succeeded in delivering sufficient doses of NO⋅ to reliably inhibit SMC growth. Since NO⋅ is a selective inhibitor of SMC, how can we increase its potency? For this work, we leverage the fact that NO⋅ increases Fas receptors on the SMC surface, while not having a similar effect on EC. Fas a death-inducing signaling complex upon binding to Fas ligand (FasL). Fas-mediated apoptosis of SMCs is known to decrease hyperplasia significantly in injured vessels. Indeed, the Fas-FasL interaction that kills SMC may create an even more potent DES than do mTOR inhibitors, since mTOR inhibition can arrest cell growth but may not cause apoptosis. Clinically, DES with better SMC inhibition are sorely needed, since current DES still suffer from significant rates of in-stent restenosis after 5 years. Since SMCs are significantly more sensitive to Fas-FasL interaction than are EC, we hypothesize that delivery of both FasL and NO by a next generation stent has the potential to potently block intimal hyperplasia, while retaining EC viability, more efficiently than other DES. This, in turn, could provide a way to shorten post-stent anticoagulation therapy and inhibit in-stent restenosis, thereby decreasing patient risk following coronary stent placement.