Cardiology, Cardiovascular Center, University Hospital Zürich, Rämistrasse 100, Zurich 8091, Switzerland.
Eur Heart J. 2014 Mar;35(12):808-20. doi: 10.1093/eurheartj/eht496. Epub 2013 Dec 11.
Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury.
PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the β-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury.
Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.
药物洗脱支架（DES）相关的安全性问题包括内皮功能障碍和支架内血栓形成。PI3K/p110α 调控细胞创伤愈合通路，因此成为损伤后调节血管稳态的新兴药物靶点。
用小分子抑制剂 PIK75 或特异性 siRNA 抑制 PI3K/p110α。在小鼠颈动脉损伤模型中研究动脉血栓形成、新生内膜形成和再内皮化。通过细胞计数和 Boyden 室分别评估人血管平滑肌细胞（VSMC）和内皮细胞（EC）的增殖和迁移。通过β-半乳糖苷酶测定评估内皮衰老，通过等长张力器官室评估内皮功能障碍。与对照组相比，PIK75 处理的小鼠动脉血栓形成延迟。PIK75 可抑制组织因子（TF）和纤溶酶原激活物抑制剂-1（PAI-1）在动脉中的表达和活性；相反，血浆凝血和血小板聚集无差异。在 VSMC 和 EC 中，PIK75 抑制 TF 和 PAI-1 的表达和活性。这些作用通过 RhoA 信号级联和转录因子 NFkB 在转录水平发生。此外，用 PIK75 或特异性 siRNA 抑制 PI3K/p110α 选择性地抑制 VSMC 的增殖和迁移，而完全保留 EC。PIK75 处理不会诱导内皮衰老，也不会抑制内皮依赖性舒张。与此观察一致，PIK75 处理选择性地抑制新生内膜形成，而不影响血管损伤后的再内皮化。
血管损伤后，PI3K/p110α 抑制选择性地干扰动脉血栓形成和新生内膜形成，但不干扰再内皮化。因此，PI3K/p110α 是 DES 设计的一个有吸引力的新靶点。
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