Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis

Arteriosclerosis, Thrombosis, and Vascular Biology
Rohun U PalekarSamuel A Wickline

Abstract

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 endotheli...Continue Reading

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Citations

Dec 8, 2016·Journal of Neurochemistry·Marta Machado-PereiraRaquel Ferreira
Dec 22, 2017·Artificial Cells, Nanomedicine, and Biotechnology·Nidhi GuptaSurendra Nimesh
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Feb 23, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Alyssa M FloresNicholas J Leeper
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Jan 27, 2020·Nanomedicine : Nanotechnology, Biology, and Medicine·Jonathan VigneIsabelle Texier
Jul 26, 2021·Nanomedicine : Nanotechnology, Biology, and Medicine·Ian VargasSamuel A Wickline

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