Department of Thoracic and Vascular Surgery, University Hospital, Laboratory of Experimental Medicine, Lausanne, Switzerland (C.D., L.M., F.A., S.D., J.-M.C., F.S., J.-A.H.); School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland (L.L., I.M., F.D., O.J.); and Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland (P.M.).
J Pharmacol Exp Ther. 2013 Dec;347(3):574-81. doi: 10.1124/jpet.113.208769. Epub 2013 Sep 26.
Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 µM) and time-dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.
内膜增生（IH）是静脉移植物狭窄的主要原因。他汀类药物等可预防狭窄，但全身给药效果有限。我们开发了一种透明质酸水凝胶基质，可确保在损伤部位阿伐他汀（ATV）的控释。释放动力学表明，无论水凝胶的加载浓度如何，100%的 ATV 在 10 小时内释放。我们研究了这种输送方式对从人静脉中分离的原代血管平滑肌细胞的影响。ATV 以相似的剂量依赖性（5-10 µM）和时间依赖性（24-72 小时）方式降低了人平滑肌细胞（HSMCs）穿过基质屏障的增殖、迁移和通过能力，无论药物是直接添加到培养基中还是从水凝胶中释放。对已知参与 IH 发展的基因进行表达分析表明，在用 ATV 加载的水凝胶孵育 24-48 小时后，缝隙连接蛋白 connexin43（Cx43）和纤溶酶原激活物抑制剂-1（PAI-1）的转录本均降低，而血红素加氧酶（HO-1）和组织型纤溶酶原激活物抑制剂的转录本增加。在蛋白质水平上，Cx43、PAI-1 和基质金属蛋白酶-9 的表达降低，而在存在 ATV 的情况下 HO-1 上调。数据表明，从水凝胶中释放的 ATV 对 HSMCs 的作用与药物在环境中自由溶解的作用相似。
