Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2448-54. doi: 10.1161/ATVBAHA.111.230078.
We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model.
One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P<0.001, n=9 group), neointimal thickness (51%, P<0.001), stenosis area (37%, P<0.001), and inflammatory score (40%, P<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P<0.05; n=6 group) and monocyte/macrophage content (by 55%, P<0.01; n=5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 μmol/L) reduced tumor necrosis factor-α (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production.
Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.
我们之前已经证明，一种选择性趋化因子蛋白（MCPs）抑制剂——比那地尔，通过减少平滑肌细胞增殖和迁移以及内膜巨噬细胞含量，从而有效抑制 MCP-1/CCL2 的产生，以此减少血管损伤的啮齿动物模型中的新生内膜形成，从而达到治疗效果。本研究的目的是评估比那地尔在临床前猪冠状动脉支架模型中抑制支架内再狭窄的疗效。
42 头猪（20 头比那地尔组和 22 头对照组）的冠状动脉中分别植入 1 或 2 个裸金属支架（Multi-Link Vision，3.5mm；扩张比 1:1.2）。从支架置入前 2 天开始，比那地尔（50mg/kg/天）每天口服给药，直至 7 天和 28 天处死。与对照组相比，比那地尔组的新生内膜面积（39.4%，P<0.001，n=9 组）、内膜厚度（51%，P<0.001）、狭窄面积（37%，P<0.001）和炎症评分（40%，P<0.001）均显著降低，而两组的损伤评分无显著差异。此外，与对照组相比，比那地尔治疗组在第 7 天和第 28 天，增殖细胞数量（减少 45%，P<0.05；n=6 组）和单核/巨噬细胞含量（减少 55%，P<0.01；n=5-6 组）分别显著减少。这些作用与 MCP-1 血浆水平在第 28 天的显著降低（P<0.05）有关。体外数据表明，比那地尔（10-300μmol/L）降低了肿瘤坏死因子-α（50ng/ml）诱导的猪冠状动脉平滑肌细胞增殖，并抑制了 MCP-1 的产生。
我们的研究结果表明比那地尔在预防猪支架内再狭窄方面具有疗效，并支持进一步研究该化合物的临床应用。
