Palekar Rohun U, Jallouk Andrew P, Myerson Jacob W, Pan Hua, Wickline Samuel A
From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.).
Arterioscler Thromb Vasc Biol. 2016 Mar;36(3):446-55. doi: 10.1161/ATVBAHA.115.306697. Epub 2016 Jan 14.
A role for thrombin in the pathogenesis of atherosclerosis has been suggested through clinical and experimental studies revealing a critical link between the coagulation system and inflammation. Although approved drugs for inhibition of thrombin and thrombin-related signaling have demonstrated efficacy, their clinical application to this end may be limited because of significant potential for bleeding side effects. Thus, we sought to implement a plaque-localizing nanoparticle-based approach to interdict thrombin-induced inflammation and hypercoagulability in atherosclerosis.
We deployed a novel magnetic resonance spectroscopic method to quantify the severity of endothelial damage for correlation with traditional metrics of vessel procoagulant activity after dye-laser injury in fat-fed apolipoprotein E-null mice. We demonstrate that a 1-month course of treatment with antithrombin nanoparticles carrying the potent thrombin inhibitor PPACK (d-phenylalanyl-l-prolyl-l-arginyl chloromethylketone) nanoparticle (1) reduces the expression and secretion of proinflammatory and procoagulant molecules, (2) diminishes plaque procoagulant activity without the need for systemic anticoagulation, (3) rapidly restores disrupted vascular endothelial barriers, and (4) retards plaque progression in lesion-prone areas.
These observations illustrate the role of thrombin as a pleiotropic atherogenic molecule under conditions of hypercholesterolemia and suggest the utility of its inhibition with locally acting antithrombin nanoparticle therapeutics as a rapid-acting anti-inflammatory strategy in atherosclerosis to reduce thrombotic risk.
临床和实验研究揭示了凝血系统与炎症之间的关键联系，提示凝血酶在动脉粥样硬化发病机制中起作用。尽管已批准的抑制凝血酶和凝血酶相关信号传导的药物已显示出疗效，但由于存在显著的出血副作用风险，它们在此方面的临床应用可能受到限制。因此，我们试图采用基于纳米颗粒的斑块定位方法来阻断凝血酶诱导的动脉粥样硬化炎症和高凝状态。
我们采用一种新型磁共振波谱方法来量化高脂喂养的载脂蛋白E基因敲除小鼠在染料激光损伤后内皮损伤的严重程度，并与血管促凝活性的传统指标进行相关性分析。我们证明，携带强效凝血酶抑制剂PPACK（d-苯丙氨酰-l-脯氨酰-l-精氨酰氯甲基酮）的抗凝血酶纳米颗粒进行为期1个月的治疗可（1）降低促炎和促凝分子的表达与分泌，（2）在无需全身抗凝的情况下降低斑块促凝活性，（3）迅速恢复受损的血管内皮屏障，以及（4）延缓易损部位斑块进展。
这些观察结果说明了凝血酶在高胆固醇血症条件下作为一种多效性致动脉粥样硬化分子的作用，并提示用局部作用的抗凝血酶纳米颗粒疗法抑制凝血酶作为动脉粥样硬化中一种快速起效的抗炎策略以降低血栓形成风险的实用性。
