Targeting integrin and integrin signaling in treating thrombosis.
Targeting integrin and integrin signaling in treating thrombosis.
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DOI：
10.1161/atvbaha.114.303411
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Du X
中科院分区：
文献类型：
--
作者：
Estevez B;Shen B;Du X
整合素在血栓形成中的关键作用使第一代整合素拮抗剂的成功开发和临床应用成为可能，以阿昔单抗(Reopro)、依替菲肽(Integrlin)和替罗非班(Aggrastat)为代表。这些整合素αIIbβ3拮抗剂是有效的抗血栓药，但也有显著的副作用。特别是，它们诱导配体诱导的整合素构象变化与血小板减少有关。出血风险的增加阻止了整合素拮抗剂在更高剂量下使用，以及在有出血风险的患者中使用。为了解决目前整合素拮抗剂引起的配体诱导的构象变化，已经开发了最小限度地诱导整合素αIIbβ3的构象变化的化合物。最近对整合素信号机制的研究表明，在动物模型中，选择性地靶向整合素由外向内的信号机制可以有效地抑制血栓形成，同时保持止血。
The critical roles of integrins in thrombosis have enabled the successful development and clinical use of the first generation of integrin antagonists as represented by abciximab (Reopro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These integrin αIIb β3 antagonists are potent anti-thrombotics, but also have significant side effects. In particular, their induction of ligand-induced integrin conformational changes is associated with thrombocytopenia. Increased bleeding risk prevents integrin antagonists from being used at higher doses and in patients at risk for bleeding. To address the ligand-induced conformational changes caused by current integrin antagonists, compounds that minimally induce conformational changes in integrin αIIb β3 have been developed. Recent studies on the mechanisms of integrin signaling suggest that selectively targeting integrin outside-in signaling mechanisms allows for potent inhibition of thrombosis while maintaining hemostasis in animal models.