Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Circ Cardiovasc Interv. 2008 Dec;1(3):209-16. doi: 10.1161/CIRCINTERVENTIONS.108.830018.
A significant fraction of vascular smooth muscle cells (VSMCs) undergo rapid apoptosis after balloon angioplasty. In this study, we tested the hypothesis that protecting VSMCs from undergoing apoptosis prevents the cascade of events that lead to intimal hyperplasia.
Rapamycin-loaded gel-like nanoparticles (mean diameter, 54+/-5 nm) were infused locally in a rat carotid artery model of vascular injury. The drug has both antiapoptotic and antiproliferative effects on VSMCs and hence was selected for the current study. Localized delivery of nanoparticles sustained the drug level in the target artery for >2 weeks; demonstrated significant inhibition of hyperplasia (intima/media ratio, 1.5+/-0.02 versus 2.7+/-0.6; P<0.01); and most importantly, re-endothelialized the injured artery (endothelium coverage: treated 82% versus control 28%). We also demonstrated inhibition of activation of caspase-3/7 enzymes in the treated artery, preventing VSMCs from undergoing apoptosis and subsequent infiltration of macrophages.
It may be postulated that the localized delivery of rapamycin inhibited apoptosis of VSMCs, minimizing the inflammatory response to the injury and, thus, creating conditions conducive to vascular repair (re-endothelialization). Unlike stenting, which can lead to thrombosis and increased risk for in-stent restenosis, our approach could eliminate or minimize long-term complications because the injured artery undergoes a natural process of re-endothelialization.
在血管成形术后，大量血管平滑肌细胞（VSMCs）迅速凋亡。在这项研究中，我们验证了一个假设，即保护 VSMCs 免受凋亡可以阻止导致内膜增生的级联事件。
雷帕霉素载药凝胶状纳米颗粒（平均直径，54±5nm）被局部注入血管损伤的大鼠颈动脉模型中。该药物对 VSMCs 具有抗凋亡和抗增殖作用，因此被选为当前研究的药物。纳米颗粒的局部给药使药物在靶动脉中的水平维持>2 周；显著抑制了增生（内膜/中膜比，1.5±0.02 对 2.7±0.6；P<0.01）；最重要的是，修复了损伤的动脉（内皮覆盖率：治疗组 82%对对照组 28%）。我们还证明了治疗动脉中 caspase-3/7 酶的激活受到抑制，阻止了 VSMCs 的凋亡和随后巨噬细胞的浸润。
可以假设雷帕霉素的局部给药抑制了 VSMCs 的凋亡，最大限度地减少了对损伤的炎症反应，从而为血管修复（内皮化）创造了有利条件。与支架置入术不同，支架置入术可能导致血栓形成和支架内再狭窄的风险增加，我们的方法可以消除或最小化长期并发症，因为受伤的动脉经历自然的内皮化过程。
